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Antimicrobial peptides: mechanism of action, activity and clinical potential
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Qi-Yu Zhang1, †, Zhi-Bin Yan1, †, Yue-Ming Meng1, †, Xiang-Yu Hong1, †, Gang Shao2, Jun-Jie Ma1, Xu-Rui Cheng1, Jun Liu3, Jian Kang4, 5, Cai-Yun Fu1, *
Military Medical Research | 2022, 9(2) : 231 - 258
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Military Medical Research | 2022, 9(2): 231-258
• REVIEW •
Antimicrobial peptides: mechanism of action, activity and clinical potential
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Qi-Yu Zhang1, †, Zhi-Bin Yan1, †, Yue-Ming Meng1, †, Xiang-Yu Hong1, †, Gang Shao2, Jun-Jie Ma1, Xu-Rui Cheng1, Jun Liu3, Jian Kang4, 5, Cai-Yun Fu1, *
Affiliations
  • 1Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou 310018, China
  • 2Department of Oncology, The 903rd Hospital of PLA, Hangzhou 310013, China
  • 3Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd. South, San Francisco, CA 94158, USA
  • 4Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia
  • 5Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia
Published: 2022-04-10 doi: 10.1186/s40779-021-00343-2
Outline
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The management of bacterial infections is becoming a major clinical challenge due to the rapid evolution of antibiotic resistant bacteria. As an excellent candidate to overcome antibiotic resistance, antimicrobial peptides (AMPs) that are produced from the synthetic and natural sources demonstrate a broad-spectrum antimicrobial activity with the high specificity and low toxicity. These peptides possess distinctive structures and functions by employing sophisticated mechanisms of action. This comprehensive review provides a broad overview of AMPs from the origin, structural characteristics, mechanisms of action, biological activities to clinical applications. We finally discuss the strategies to optimize and develop AMP-based treatment as the potential antimicrobial and anticancer therapeutics.

Antimicrobial peptides  /  Antimicrobial resistance  /  Mechanism of action  /  Biological activity  /  Clinical application
Qi-Yu Zhang, Zhi-Bin Yan, Yue-Ming Meng, Xiang-Yu Hong, Gang Shao, Jun-Jie Ma, Xu-Rui Cheng, Jun Liu, Jian Kang, Cai-Yun Fu. Antimicrobial peptides: mechanism of action, activity and clinical potential[J]. Military Medical Research, 2022 , 9 (2) : 231 -258 . DOI: 10.1186/s40779-021-00343-2
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Background
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Antimicrobial peptides (AMPs) are the small molecular peptides that play a crucial role in the innate immunity of the host[1] against a broad range of microorganisms, including bacteria, fungi, parasites and viruses[2-4]. To date, the AMP database [Data Repository of Antimicrobial Peptides (DRAMP), http://dramp.cpu-bioinfor.org/] has reported 3791 AMPs from six kingdoms, including 431 from bacteria, 4 from archaea, 7 from protozoal, 6 from fungal, 824 from plants and 2519 from animals[5]. Besides antibacterial activities, AMPs have been found to possess a variety of biological functions, such as immune regulation, angiogenesis, wound healing and antitumor activity[6-9]. The treatment of pathogenic bacteria has been long-time mainly relied on antibiotics. However, the emergence of drug resistance due to the single target of antibiotics, long-term and extensive utilization, is becoming a major challenge for clinical infection management[10,11]. In contrast, AMPs show the advantages by acting on multiple targets on the plasma membrane and intracellular targets of pathogenic bacteria, and have potent activity on drug-resistant bacteria[4,12,13]. Thus, AMPs provide a new alternative to antibiotics. Furthermore, the long-term chemotherapy in cancer patients not only leads to resistance to conventional cancer treatments, but also results in the susceptibility to pathogenic infection. AMPs have antibacterial and anticancer properties, and thus is a new treatment option for cancer patients. At present, the clinical application of AMPs is mainly on the treatment of pathogenic bacteria infection, wound healing and inflammation[14,15]. While a few AMPs have entered the clinical stage of cancer treatment, the inevitable defects in the natural AMPs are the obstacles to development of AMPs with therapeutic efficacy. Therefore, to overcome these shortcomings, it is essential to further explore the structural characteristics and mechanism of action of AMPs to improve their stability, activity, targeting, and reduction of cytotoxicity. This review extensively overviews the origin, structural characteristics, mechanisms of action and biological activity of AMPs with the aim to provide the comprehensive current knowledge and understanding of AMPs and more importantly, the new prospects for clinical development and applications of AMPs.
Natural distribution of AMPs
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As an ancient host defense mechanism against pathogen invasion, AMPs are well preserved in eukaryotes. This is because that: 1) as a component of the innate immune system, production of AMPs by the host cells requires less time and energy than antibody synthesis by the acquired immunity; 2) these small molecule peptides can reach the target faster than immunoglobulins; and 3) some eukaryotes lack of lymphocyte-based immune system, such as insects mainly rely on the synthesis of a series of antibacterial compounds to remove invading microorganisms[16]. Since the first AMP was discovered in the American silkworm chrysalis, a large number of AMPs have been widely found in various organisms, including microorganisms[17], plants[18], invertebrates[19], fish[20], amphibians[21], reptiles[22], birds[23] and mammals[24].
The first AMP isolated in bacteria is nisin, which produced by the host strain has cytotoxicity to other types of bacteria in order to compete for nutrients in the environment[25]. In recent decades, nisin has been widely used as a natural preservative in many foods due to its antiseptic activity[26-28]. AN5-1 was originally isolated from the fermentation broth of Paenibacillus alvei strain[29]. It destroys the bacterial membrane and inhibits cellular functions by integrating and disrupting the bacterial genomic DNA[30]. Besides, recent studies reported that intestinal microbiota served as a source of AMPs[31,32]. AMPs have also been found in fungi[17]. In addition, Copsin originated from Coprinopsis cinerea (Mushroom), has bactericidal effects on a variety of Gram-positive bacteria by interfering with the biosynthesis of the cell wall of pathogens, such as Enterococcus faecalis (E. faecalis) and Listeria monocytogenes (L. monocytogenes)[33].
AMPs also protect plants from the invasion of pathogenic microorganisms in the air and soil. There are multiple families of plants-derived AMPs, including thionins, defensins and cyclotides[34]. Thionins are widely found in seeds, stems, roots and leaves of plants[35] and have cytotoxic effects on Gram-positive bacteria[36], Gramnegative bacteria[36], yeasts[37] and other fungi[38]. Plants-derived AMPs are usually rich in cysteine residues to form multiple disulfide bonds that are important for structural stabilization[39].
Due to lack of lymphocyte-based immune system, invertebrates mainly rely on the innate immune system as the first line of host defense to resist the invasion of pathogenic bacteria[40]. Invertebrate AMPs are widely distributed in hemolymph, mucosa of skin and other tissues. For example, cecropins derived from hemolymph of Hyalophora cecropia, have a strong antibacterial effect on Gram-positive and Gram-negative bacteria[41]. The induced expression of drosocin in the intestinal tract of drosophila can prevent the infection of pathogen Pseudomonas entomophila[42] and thus maintain intestinal homeostasis. The Toll and Imd pathways are the important pathways in regulation of AMP production in drosophila[43], and the similar regulatory pathways have also been found in mammals[44].
Together with inorganic substances (hydrogen peroxide and nitric oxide), antibacterial proteins (such as lysozyme, azurocidin, cathepsin G, phospholipase A2 and lactoferrin), AMPs constitute the innate immune system of mammals[45]. To date, more than 1770 species of AMPs have been found in vertebrates. Most mammals mainly have the two classes of AMPs termed cathelicidins and defensins[46,47], and fish also contains hepcidins and piscidins[48].
Cathelicidins are a class of AMPs which have a highly conserved cathelin domain and the distinct peptide lengths, amino acid sequences and protein structures[49]. They are stored in a nonfunctional form in neutrophils and macrophage secretory granules and become activated after being processed and released upon leukocyte activation[46]. Cathelicidins (CATH BRALE and codCath1) derived from fish show potential antibacterial activity to a broad spectrum of Gram-positive and Gram-negative bacteria[50]. Skin is an important source of AMPs for amphibian[51]. Cathelicidin-PV, an AMP identified in the skin of the frog Paa yunnanensis, has strong antibacterial activity against Gram-positive and Gram-negative bacteria, fungi, as well as clinically isolated drug-resistant and standard strains but has low hemolytic activity[52]. Cathelicidin-related peptide (crotalicidin) has been identified in the rattlesnake of South America. Both crotalicidin and its fragments (15–34) have potential antibacterial, anti-tumor and anti-fungal properties[53]. These peptides killed 90% of Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) cells within 90–120 min and 5–30 min, respectively. In addition, cathelicidins are also found in birds[54], cattle[55], horses[56], pigs[57], goats[58-60], sheep[61], chickens[62,63], dogs[64] and rabbits[65]. Notably, LL-37 is the only cathelicidin that is found in humans[66].
Another group of AMPs is defensins. They are divided into three subtypes based on the arrangement of disulfide bonds including α-, β- and θ-defensins[67,68]. α-defensins and θ-defensins evolved from an ancient β-defensins[69]. In humans, there are only α-defensins and β-defensins but no θ-defensins due to an early termination codon in the mRNA. Reptiles and birds only produce β-defensins while θ-defensins are found in the leukocytes and bone marrow of some non-human primates[46,47,69]. Similar to cathelicidins, α-defensins are cleaved by elastase, metalloproteinase or other proteolytic enzymes and ultimately formed a C-terminal peptide with potential antimicrobial activity[70]. The first β-defensin is found in the epithelial cells of cattle[71]. Turtle β-defensin 1 (TBD-1) is the first β-defensin isolated from leukocytes in reptiles with a high homology to β-defensins from birds and mammals[72]. Wang et al.[73] showed that 11 bacteria (including Gram-positive and Gram-negative bacteria) were almost completely killed by AvBD9, a kind of β-defensins derived from quail, at the concentration of 25 μg/ml.
As the key component in the innate immunity, AMPs are generated in the sites where the body is most vulnerable to pathogen invasion. In mammals, the AMPs-rich mucus resists the colonization of parasites, bacteria and fungi[74,75]. AMPs are also found in phagocytic granulocytes and mast cells[76]. The α-defensins in mammals mainly exist in neutrophils, macrophages and intestinal Paneth cells, while β-defensins exist more extensively including leukocytes and epithelial cells in the skin, the respiratory, digestive and genitourinary tracts, as well as the blood and urine[77]. The human β-defensin 3 (HBD3) also exists in the heart and skeletal muscle[77]. While the eyes are always exposed to the outside and at the risk of pathogenic bacterial infection at all times. The AMPs in eyes play a key role in infection prevention[2]. Cathelicidins are originally isolated from bone marrow cells[78]. Similar to defensins, most cathelicidins are stored in the granules of neutrophils or macrophages and can be secreted by epithelial cells and immune cells[46,79] and widely distributed in mucosal secretions, blood, urine, sweat and tears[80-83]. Characterization of the structure and physiochemical features of AMPs can help us to identify the novel AMPs. The new technologies, such as the new genome mining approaches using machine learning and sequence-based encodings[84] will accelerate this discovery process.
Structure and characteristics of AMPs
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AMPs are divided into several subgroups on the basis of amino acid sequences, the net charge of the peptide, protein structure and sources (Additional file 1: Table S1). Most AMPs have a net charge of +2 to +9 and contain 10–100 amino acids[85]. The Database of Antimicrobial Activity and Structure of Peptides (DBAASP, https://dbaasp.org/) is an open-access, comprehensive database containing information related to amino acid sequences, chemical modifications, 3D structures, bioactivities and toxicities of peptides that possess antimicrobial properties. The latest version 3.0 (DBAASP v.3) contains >15,700 entries (8000 more than the previous version)[86].
The first subgroup is the anionic AMPs which have a net charge range of −1 to −8 and contain 5 to 70 amino acid residues[87]. The majority of anionic AMPs are the peptide fragments after proteolysis but some anionic AMPs are the small molecules encoded by genes. Their structure features include α-helical peptides from some amphibians and cyclic cystine knots[87]. They seem to utilize metal ions and the negatively charged components of the microbial membrane to form salt bridges, thus interacting with microbes[88], which are similar to the charge-neutralization characteristics of larger proenzyme[89]. For example, ovine pulmonary surfactant associated anion peptide (SAAP), the first discovered anionic AMP with 5–7 aspartate residues, had antimicrobial activity to the ovine pathogen Mannheimia haemolytica in the presence of Zn ions[90]. When 0.14 mol/L NaCl and EDTA were added into the surfactant solution, its bactericidal activity was largely inhibited, while restored when ZnCl2 was replenished. In addition, the amidated C-terminal fragment of the α-helical anionic AMP maximin H5 forms an intra-peptide hydrogen bond with the N-terminal region of the peptide, important for stabilizing the tilted α-helix structure[87].
The second subgroup is the cationic α-helical AMPs. These small peptides with less than 40 amino acids in length, carry a net charge of +2 to +9 and mostly have the C-terminus amidated[91]. The structure of these peptides is disordered in aqueous solutions, but in the presence of trifluoroethanol, sodium dodecyl sulfate (SDS) micelles, phospholipid vesicles, and liposomes or liposomes A, the molecules are all or partly transformed into α-helical structure[92]. In addition, these AMPs usually contain over 50% hydrophobic amino acids, which enable the formation of amphiphilic structure when interacting with target cells[93]. Most cathelicidins are amphiphilic α-helical AMPs[6], in which cecropins, magainins and LL-37 have been well studied. LL-37 is the only human cathelicidin of an active fragment released from hCAP18 by serine protease 3 in neutrophils with a net charge of +6 at a neutral pH[94,95]. The circular dichroism of LL-37 shows a disordered structure in water and is transformed into an α-helical structure in the presence of HCO3−, SO42−, or CF3CO2− at the concentration of 15 mmol/L[96]. The efficiency of structural transformation is directly proportional to the concentrations of the peptide. Moreover, the degree of α-helix is correlated with the antibacterial activity of LL-37 against Gram-positive and Gram-negative bacteria.
The third subgroup is the cationic β-sheet AMPs. The peptides typically contain 2–8 cysteine residues forming 1–4 pairs of intramolecular disulfide bonds[97]. The disulfide bonds are essential for structure stabilization and biological functions of these peptides. For example, they become inactivated when cysteines are replaced by acidic amino acids, while remain active when mutating to hydrophobic amino acids (excluding alanine and leucine)[98]. However, the structure and disulfide bonds of human neutrophilic peptide 1 (HNP1), HBD3 and mouse defensins are not required for antimicrobial activity or cytotoxicity[70,99]. The β-sheet AMPs consist primarily of defensins[97]. As mentioned above, the mammalian defensins are classified as α-defensins and β-defensins according to the characteristic intervals between the six cysteine and disulfide bond modes[100]. Despite difference in covalent structures, the mammalian defensins display very similar tertiary structures[101]. In the case of α-defensins, near the amino terminus they form a three-stranded chain by hydrogen bonding with the β-hairpin, and a cyclic structure by pairing cysteine with disulfide bonds[101]. The bactericidal activity of amphipathic α-defensins depends on the positive charge and hydrophobic amino acids that cause bacterial membrane destruction by interacting with phosphatidyl chains[102]. Moreover, the interaction between cationic α-defensin residues and negatively charged substances on the bacterial surface may precede the interaction between hydrophobic residues and the membranes and thus primarily mediate membrane destruction and bacterial killing. In the case of β-defensins, some defensins contain both α-helix and β-sheet. For instance, the insect defensin A, has an α-helix of 11 amino acids in the middle (residues 14–24), and its N-terminal β-hairpin is parallel to the α-helix with a cyclic structure formed by the first 13 amino acid residues[103]. The antibacterial and antiparasitic activities are predominantly mediated by the N-terminal domain of the chicken Gga-AvBD11 and enhanced by its C-terminal domain while the antiviral activity requires the full-length protein[104]. The θ-defensins are the end-to-end cyclized tetracyclic peptides that have three disulfide bridges to connect their antiparallel β-sheets[105]. The cyclic structure of the θ-defensins allows them to remain active at high concentration of salt and is essential for their antimicrobial properties supported by decrease of the microbicidal activities caused due to loss of the cyclic structure[106]. Recent studies further reveal that the structure and stability of defensins mainly depend on the number and position of the disulfide bonds, while their antibacterial and membrane-binding properties rely on the cyclic backbone[107].
The fourth subgroup is the extended cationic AMPs containing the specific amino acids including arginine, proline, tryptophan, glycine and histidine, but lacks regular secondary structures[93]. Their structures are stabilized only by hydrogen bonds and van der Waals force of interacting with the membrane lipids. Typically, PR-39 is rich in proline (49%) and arginine (24%)[108], prophenin-1 is rich in proline (53.2%) and phenylalanine (19%)[109], indolicidin is rich in tryptophan (38%) and proline (23%)[110], and histatin-8 is rich in histidine (33.3%)[111].
The fifth subgroup is the fragments from antimicrobial proteins. Some naturally occurring proteins and their fragments have a broad-spectrum bactericidal effect. Lysozyme, the first discovered antimicrobial protein, is a key component of the innate immune system against foreign pathogens[112-114]. Its extracellular fragment contains 130 amino acids and has an α-helix and β-sheet structure. A helix-loop-helix (HLH) region in the lysozyme of human and chicken has been also found in other membrane active and DNA binding proteins[115]. The HLH peptide has a strong bactericidal effect against Gram-positive and Gram-negative bacteria, and the fungus Candida albicans (C. albicans). More recently, Toda et al.[116] identified a sleep-inducing gene in fruit flies encoding NEMURI protein which contains an arginine-rich region, and possessed immunomodulatory functions and strong bactericidal effect comparable to that of kanamycin. Other antibacterial proteins are shown in Additional file 1: Table S1.
Notably, some AMPs contain the amino terminal copper and nickel (ATCUN) binding motif. It is composed of the sequence H2N-XXH found in the N-terminus, where the XX can be any amino acid other than proline[117]. Cu2+ and Ni2+ can bind to the motif with a high affinity[118]. The Cu2+-ATCUN complex can produce reactive oxygen species (ROS)[119,120], which target nucleic acids, proteins and lipids[118].
Targeting specificity of AMPs
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The central question in the research of AMPs is how AMPs these peptides specifically target the invading pathogen while spare the host cells? The differences in the composition of cell membrane between the pathogens and the host cells have been considered to underpin the targeting specificity of AMPs. In general, the lipids and proteins are the main components of the cellular membrane and form the phospholipid bilayer as the basic scaffold for the cell membrane. Phosphatidylcholine (PC) and phosphatidyl ethanolamine (PE) are normally uncharged, while hydroxylated phospholipids such as phosphatidylserine (PS), cardiolipin (CL) and phosphatidylglycerol (PG) are negatively charged. Intriguingly, PS, PG and CL are found in bacterial pathogens but have little or no presence in mammalian cytoplasmic membrane[121,122]. In contrast, PE and PC are commonly found in mammalian cell membranes[122]. In addition, sterols such as cholesterol (mammalian) and ergosterol (fungi) are present in eukaryotes but rarely in prokaryotic cell membranes[123,124]. Moreover, the lipopolysaccharide (LPS) of Gram-negative bacteria and the lipoteichoic acid of Gram-positive bacteria carry a large number of negative charges, which increases the amount of negative charge of the membrane. Different from bacteria, the negative charges of the fungal membranes mainly resulted from the phosphomannan and other related components, such as negatively charged phosphatidylinositol (PI), PS and diphosphatidylglycerol (DPG)[125]. Consequently, the cationic AMPs selectively interact with the negatively charged membrane through electrostatic interaction which partially explains the targeting specificity of AMPs.
Compared with normal cells, cancer cells also exhibit more negatively charged PS outside of membrane[126]. Furthermore, the high expression of glycoproteins that contain repeated regions of O-glycosylation[126] and some other anionic components such as gangliosides and heparan sulfates on the membrane surface of cancer cells also contribute to the negative charge on the surface[127,128]. In addition, the presence of a large number of microvilli on the membrane surface of cancer cells increases the area available for AMPs binding[129].
Mechanism of action of AMPs
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Membrane model
The cationic AMPs exert antibacterial activity by interacting with negatively charged bacterial membrane to increase membrane permeability and lead to cell membrane lysis and cell content release. Upon approaching the cytoplasmic membrane through electrostatic interaction with the microbial membrane, AMPs bind to the microbial membrane and interact with the anionic components of the plasma membrane. Prior to this, AMPs have to pass through the capsular polysaccharide and other components of the cell wall, such as LPS of Gram-negative bacteria and lipoteichoic acid and peptidoglycan of Gram-positive bacteria[130-132]. In this step, there are two major factors that affect the interaction, namely the conformational change and the peptide-lipid ratio[133-136]. Studies have shown that α-helical AMPs bind to the anionic lipid membrane and transformed its disordered structure in aqueous solution into the amphiphilic α-helical structure to facilitate the interaction with the membrane[137]. Different from α-helical peptides, the β-sheet peptides do not undergo a major conformational transition when interacting with the membrane due to their stable disulfide bond bridge[137]. The peptide-lipid ratio is another major factor that affects AMP interaction with cell membrane. At a low peptide-lipid ratio, AMPs are located in parallel on the surface of the plasma membrane[138,139]. With the increase of the peptide-lipid ratio, AMPs are vertically oriented and inserted into the hydrophobic center of the membrane. Eventually, membrane permeation leads to the leakage of intracellular ions, metabolites and biosynthesis, with the consequent cell death[140].
Some hypothetical models of membrane-cavity formation, such as barrel-stave, toroidal-pore, carpet and aggregate models, have been proposed (Fig. 1). In the barrel-stave model, with the increased amounts of peptide binding to the membrane, aggregation and conformational transformation occur, which causes local phospholipid head groups shift and membrane thinning[141]. During the process of penetration into the phospholipid bilayer, the helical hydrophobic regions of the α-helical peptides and β-sheet peptides are close to the hydrophobic regions of the membrane phospholipid, while the hydrophilic regions of the peptide helixes are inwards, and multiple helical molecules are arranged in parallel to form the central lumen[137].
While the mechanism of toroidal-pore model is similar to that of barrel-stave model, the difference is that in the toroidal-pore model the peptide helixes insert into membrane and bind with lipids to form toroidal pore complexes. Locally accumulated AMPs at high concentrations induce deformation of bending in lipid molecules, thus enabling the peptides and lipid head groups embedded inside of the lipid hydrophobic center[141].
In the carpet model, while the electrostatic effect of AMPs and anionic membrane is necessary, the high AMP concentrations are required to form micelle and destroy the microbial membrane[137]. When the peptide concentration reaches the threshold, AMPs cover the membrane in clusters and cause the membrane rupture in a surfactant-like manner. Neither channel formation nor insertion of the peptides into the hydrophobic center of the membrane occurs. This effect is potent enough to induce the completely or partially cell membrane lysis with the result of cell death.
In the aggregate model, AMPs bind to the anionic cytoplasmic membrane, forcing the peptides and lipids to form a peptide-lipid complex micelle[142]. Different from the carpet model, the channels formed by AMPs, lipids and water allow ions and intracellular contents to leak out, and then lead to cell death. These channels may also help AMPs transfer into the cytoplasm and exert function. This mechanism explains why AMPs not only target the cytoplasmic membrane, but may also cross the membrane into the cytoplasm to act on intracellular substances[143].
Unlike the cationic AMPs, the mechanisms of anionic AMPs action remain elusive. The antibacterial mechanism of maximin H5 against Staphylococcus aureus (S. aureus) has been considered to be associated with the membrane dissolution[144]. The maximin H5 interacts with microorganisms through its N-terminal α-helical peptide where the aspartic acid residues only play a major structural role due to their distance to the membrane surface. Hydrogen bonds formed by amidation of C- and N-terminal is crucial for stabilizing the α-helix structure of the peptide[87]. Besides, low pH appears to help enhancing the degree of α-helix of maximin H5 and promotes to kill S. aureus in a “Carpet”-like mechanism[144]. The anionic AMP Xlasp-p1 exhibits a significant broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria by destruction of cell membranes and intracellular material efflux[145]. A recent study reported that the anionic AMP AP2 reduced the survival of C. albicans cells, but had no effect on the activity of protoplast, suggested AP2 may act on fungal cell walls[146].
In addition to destruction of membrane, other modes of action have also been reported. For instance, in neutral pH, clavanin A adopts the membrane permeation mode of α-helical peptide[147]. But in slightly acidic pH, it induces cell death by acting proteins on the membrane that maintain a stable pH gradient. The LPS anchored in the outer membrane of the bacterial pathogen is a crucial step for microbial surface disruption. Fiorentino et al.[148] illustrated that insertion of LPS into the bacterial surface relies on the concerted opening movements of both the β-barrel and β-taco domains of LPS transport protein. Thanatin stabilizes the β-taco domain, thereby preventing transport of LPS to the cell surface[148].
Intracellular mode of action
A growing body of evidence suggested that AMPs had other mechanisms along with membrane penetration and pore formation (Fig. 1).
AMPs acting on nucleic acids
Buforin II, an AMP with 21 amino acids in length, has antibacterial activity against a wide range of bacteria[149]. It has the same sequence as the part of the histone H2A, a protein that directly interacts with nucleic acids[149]. Previous studies have shown that buforin II penetrated lipid vesicles in vitro without affecting membrane permeability and bound to DNA and RNA[149]. Another study indicated that buforin II mutants exhibited a reduced interaction with DNA and activity compared with buforin II[150]. Similarly, indolicidin penetrated bacterial membranes and inhibited DNA synthesis in the absence of bacterial cell lysis[149]. Peptide-P2, an anionic antimicrobial peptide isolated from Xenopus laevis skin, inhibited bacterial growth by disruption of the bacterial cell membrane, and interaction with the microbial genomic DNA[151]. In addition to directly binding to DNA and inducing DNA damage, AMPs can also indirectly inhibit the DNA replication or transcription[152-154].
AMPs acting on protein synthesis
PR-39, an proline and arginine-rich AMP and isolated from the small intestine of pigs, was found to penetrate the outer membrane of E. coli rapidly[155]. Once entry into the cytoplasm, PR-39 inhibits protein synthesis and causes the degradation of proteins required for DNA synthesis, which in turn disrupt DNA synthesis. Typically, the proline-enriched AMPs interfere with protein synthesis via binding to ribosomes[156]. For example, oncocintype peptide inhibits mRNA translation by binding 70S ribosome export, while apidaecin-type peptide blocks the assembly of the ribosome 50S large subunit[157]. Api137, an apidaecin-derived peptide, was showed to bind E. coli ribosomes and trap release factor 1 (RF1) or release factor (RF2) for releasing the nascent polypeptide chain, resulting in translation termination[158]. Another study showed that the N-terminal fragments (1–25) and (1–31) of nonlytic proline-rich AMP (PrAMP) Bac5 inhibit bacterial protein synthesis by binding the tunnel of ribosome and preventing the transition from the initial stage to the elongation stage of translation[159].
AMPs acting on the activity of enzyme
Reports have indicated that AMPs inhibit the activity of bacterial intracellular enzyme[133]. Otvos’ group showed that a PrAMP pyrrhocoricin specifically bound bacterial heat shock protein DnaK from E. coli protein lysates[160]. In a follow-up study, the same group demonstrated that pyrrhocoricin inhibited the ATPase actions of DnaK[161]. A ribosomal synthesized and post-translationally modified peptide, microcin J25 was found to bind to the secondary channel of the RNA polymerase and block trigger-loop folding, which is essential for efficient catalysis by the RNA polymerase. Consequently, it inhibits RNA polymerase activity by preventing the entry of substrates through this channel[162]. Yang et al.[163] discovered that LL-37 had a dramatic antibacterial effect on E. coli via the inhibition of activity of palmitoyl transferase PagP, which is located in the Gram-negative bacterial cell outer membrane and repairs membrane permeability through activation of lipid A acylation. Hou et al.[164] suggest that the antimicrobial peptide NP-6 from Sichuan pepper seeds strongly inhibited the β-galactosidase activity of E. coli in a dose-dependent manner.
AMPs acting on the synthesis of cell wall
HNP1 was initially found to penetrate the outer and inner membranes of E. coli and suppress the synthesis of DNA, RNA and protein of bacteria[165]. Notably, inner membrane permeabilization appears to be the lethal event. The antibacterial activity of cycloserine can be inhibited by cycloserine which blocks the activity of alanine racemase and D-Ala-D-Ala ligase and consequently the synthesis of D-Ala-D-Ala dipeptide of lipid II of the peptidoglycan precursor[166]. This suggests that HNP1 kills bacteria by interacting with lipid II. Teixobactin inhibits the synthesis of cell wall by binding to a highly conserved motif of lipid II and lipid III (precursors of cell wall teichoic acid)[167]. Manabe et al.[168] found that D-form KLKLLLLLKLK-NH2 peptide enhanced the membrane permeability of S. aureus through specifically integrating with cell wall components (including peptidoglycan), thus having higher antibacterial activity than L-form.
AMPs acting on other targets
Pyrrhocoricin, drosocin and apidaecin, the short PrAMPs, interact with the heat shock protein DnaK of bacterial to exert antibacterial effects[161]. Drosocin and pyrrhocoricin inhibit chaperone-assisted protein folding via binding of DnaK. The θ-defensins are the circular AMPs produced in the leukocyte of Old World monkeys. These AMPs interact with bacterial membrane. The release of cell wall lyase further hydrolyzes the sugar chain and peptide bridge of the murein, and eventually induces Staphylococci lysis[169]. For example, Mel4 induced cell death of S. aureus by inducing the release of bacterial autolysin[170]. In addition, AMP PFR induces necroptosis by endoplasmic reticulum (ER) stress, and elevated cytoplasmic calcium and mitochondrial ROS levels[171].
Recent studies suggest that the direct coaggregation of amyloidogenic peptide and amyloids is an important antibacterial mechanism of AMP action[172]. Despite the low similarity between AMPs and amyloidogenic peptides in terms of sequences, typical secondary structures, or normal biological activity, the facts of the formation of fibrils by antimicrobial peptides and the antimicrobial activity of amyloidogenic proteins indicate a potential similarity in actions[173]. Indeed, Kurpe et al.[174] demonstrated that the amyloidogenic regions of ribosomal S1 protein from Thermus thermophilus can act as antibacterial peptides, interacting with the “parental” S1 protein (protein of specific bacterial species) to form fibrils that aggregate and interfere with its function. The formed protein aggregates can also suppress the intracellular transport processes, sorb chaperones and the functions of other proteins and ultimately, lead to the bacterial death[172]. Interestingly, amyloidogenic regions are predicted in about half of the AMP[172], implicating the potential significance of aggregation in AMP action.
Activity of AMPs
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Antibacterial activity
AMPs exert antibacterial activity by membrane or nonmembrane mediated action. As discussed above, the cationic AMPs have a stronger affinity with microbial pathogens due to the presence of the unique anionic components in the plasma membrane of bacteria and fungi, such as LPS of Gram-negative bacteria, lipoteichoic acid of Gram-positive bacteria and mannan of fungi. AMPs cause membrane permeation or perforation to induce the leakage of intracellular contents, or penetrate into the membrane to exert intracellular actions. The rapid killing and generic membrane and intracellular effects without targeting specific molecules/pathways prevent the development of bacterial resistance to AMPs. Therefore, it is attractive to the application of AMPs to the management of antibacterial resistance. Bacteriocins are a large class of small molecule cationic AMPs (30–60 amino acids) isolated from bacteria. According to the mechanisms of peptide synthesis, they were classified into two groups. One group is the peptides synthesized by ribosomes with relatively narrow antibacterial activity against bacteria and fungi, and the other group is the peptides synthesized by non-ribosomes with broad antibacterial activity[175]. Wang et al.[176] discovered a new short non-ribosomal AMP, albopeptide 6, in the culture broth of Streptomyces albofaciens, which displayed a narrow-spectrum activity against vancomycin-resistant Enterococcus faecium. Nisin is a member of the bacteriocins family and has high antibacterial activity against a wide range of Gram-positive bacteria and even Gram-negative bacteria[177]. Tong et al.[178] reported that penicillin or chloramphenicol combined with nisin improved antibacterial effect in E. faecalis where single antibiotic alone had no significant activity. Therefore, AMPs act as the novel therapeutic option of treating antibiotic-resistant bacteria either alone or applied in a synergistic manner. It is found that the expression of AMPs in shrimp, such as CrusI-3 and Alf-E1, are directly regulated by the forkhead box transcription factor O (FoxO) but independent of the Imd signaling pathway[179]. Notably, the long-term exposure to a low concentration of AMPs can induce the resistance[180]. Thus a high concentration of AMPs is recommended for maintaining the bactericidal activity[180].
Antiviral activity
Besides the antibacterial activity, AMPs also have a broad-spectrum antiviral activity against the enveloped viruses. For example, bovine antimicrobial peptide-13 effectively inhibits the viral proliferation by disruption of the viral protein synthesis and the viral gene expression in transmissible gastroenteritis virus[181]. The anti-herpes simplex virus (HSV) activity of AMPs, such as protegrin and indolicidin, have been attributed to blocking the adhesion and entry of the virus by targeting the viral membrane glycoprotein[182,183]. The inhibitory effect of LL-37 on a variety of the enveloped viruses, including human immunodeficiency virus (HIV), influenza A virus (IAV), vaccinia virus (VV), HSV, dengue virus (DENV) and Zika virus (ZIKV)[184-189], is achieved by destroying the viral membrane and inhibiting DNA replication. Additionally, LL-37 and mouse CRAMP markedly inhibit non-enveloped enterovirus 71 replication via regulating antiviral response and inhibiting viral binding[190]. LeMessurier et al.[191] have demonstrated that AMPs altered the immune response to IAV infection, thereby enhancing the protection of the host against virus. Both pa-MAP and temporin B reduce the infection of HSV1 by inhibiting the attachment of the virus[192,193]. In addition, temporin B can also destroy the virus envelope and affect the subsequent post-infection stage. Temporin G, an analogue of temporin B, showed the ability to interact with the viral hemagglutinin protein of influenza virus and consequently block the conformational rearrangements of HA2 subunit, a process which is essential for the viral envelope fusion with intracellular endocytic vesicles and the entry into the host cells[194]. In the case of parainfluenza respiratory virus, the temporin G-mediated blocking of the late steps of viral replication impairs the extracellular release of viral particles. The human α-defensin-derived peptide HD5(1–9) is also able to prevent viral infection by inhibiting the adherence and the subsequent entry of the virus into cells[195]. Cathelicidin-derived AMP GF-17 and BMAP-18 inhibit ZIKV through directly inactivating the virus and interfering with the interferon (IFN) pathway[196]. Furthermore, other AMPs also have antiviral activities against DENV and pseudorabies virus[197,198]. Moreover, AMPs have also been reported to fight against non-enveloped viruses. For instance, LL-37 has been shown to be against non-enveloped viruses such as adenovirus, rhinovirus and Aichi virus[192,199,200]. AMPs not only exert a direct antiviral effect on the viral particle and its replication cycle, but also indirectly inhibit virus growth by regulating host immune response[201,202] as discussed below. Recent studies have reported that vitamin D can induce the production of cathelicidins and defensins to reduce the rate of virus replication, thereby reducing the risk of infection and death from influenza and coronavirus disease 2019 (COVID-19)[203].
Antiparasitic activity
A large body of literature had focused on the role of AMPs in the activity of antibacterial and antiviral, however, there is still a paucity of reports about antiparasitic activity, particularly in vivo and in clinical settings. The diversity of parasite is very large, ranging from protozoa to worms. Parasites are an important cause of the human diseases worldwide, resulting in a significant global health burden[204,205]. Eleven parasitic infections have been identified by the World Health Organization (WHO) as neglected tropical diseases because they threaten the health of millions of individuals and disproportionately impact impoverished individuals[205]. The most important parasitic diseases including malaria, leishmaniasis, trypanosomiasis and schistosomiasis[206,207]. AMPs-based antiparasitic therapeutic strategies has gained the substantial interest recently. Leishmanicidal AMPs have been found in different creatures, for example: 1) halictine-2, from the venom of eusocial honeybee, showed significant anti-leishmanial activity without haemolytic activity for mouse macrophages and human erythrocytes[208]; 2) attacin, cecropin and defensin 2 from Lutzomyia longipalpis by Toll and Imd pathways, respond to Leishmania infantum chagasi infection[209]; and 3) dragomide E, a linear lipopeptide isolated from the cyanobacteria Lyngbya majuscula with an antileishmanial activity against Leishmania donovani promastigotes. In addition, LZ1, a peptide derived from snake cathelicidin, showed strong suppression of blood stage Plasmodium falciparum by specifically inhibiting adenosine triphosphate (ATP) production in parasite-infected erythrocyte[210]. Phylloseptin-1, from the skin secretion of Phyllomedusa azurea, had high antiparasitic activity and prevented the development of cross-resistance because of its unique chemical structure[211].
Immunomodulatory activity
AMPs, also known as the host defense peptides, protect the host from infection through antimicrobial activity and immunomodulatory effect[212-215]. The invasion of pathogens activates a series of immune responses (Fig. 2). Neutrophils are the major source of cathelicidins and defensins[6,46]. The role of AMPs in the immune process is extremely complex. AMPs maintain the dynamic balance of the immune microenvironment through regulating the section of cytokines, such as interleukins, tumor necrosis factors (TNFs), IFNs, chemokines, and activities of immune cells such as dendritic cells (DCs), monocytes, macrophages, mast cells, granulocytes and lymphocytes. These peptides regulate the cell surface receptors such as cytokine receptors, chemokine receptors and G-protein coupled receptors (GPCRs) including formyl peptide receptors (FPRs) and Toll-like receptors (TLRs), and several intracellular signal pathways such as nuclear factor-κB (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), p38, JUN N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K).
As a component of the innate immune system, AMPs interact with immune cells to eliminate pathogens and prevent infection. LL-37 is constitutively expressed by neutrophils[66], mast cells, natural killer (NK) cells and epithelial cells[216], and recruits other immune cells to the sites of microbial invasion by binding to peptide receptor-like 1 (FPR1) (newly named FPR2)[217-219]. LL-37 also promotes the migration of mononuclear/macrophage and significantly enhances macrophage phagocytosis against Gram-positive and Gram-negative bacteria by interacting with the primary receptor integrin αMβ2 (Mac-1) on the bone marrow cell surface[220]. Moreover, LL-37 induces cell chemotaxis and degranulation, and recruits mast cells to inflammatory lesions by binding to GPCR Mas-related gene X2 (MrgX2) on mast cells[220]. LL-37 is also shown to promote the formation of neutrophil extracellular traps (NETs)[216,221] and stabilized neutrophil derived DNA or NETs to resist being degraded by bacterial nuclease. In addition, LL-37 induces activation of caspase-1, and processing and release of IL-1β through binding to P2X7 receptor in LPS-primed macrophages[222], and promotes ROS production in neutrophil[223].
LL-37 evokes the inflammatory response by stimulating immune cells to secrete chemokines and proinflammatory cytokines. It directly stimulates mast cells to synthesize IL-1β, IL-6, TNFs and chemokines including CCL2 and CCL3 but not CCL8[224]. It also causes the enhancement of TLR2, TLR4 and TLR9 on the mast cell surface and TLR3, TLR5 and TLR7 in the cytoplasm, perhaps by regulating the expression of TLR to enhance the ability of mast cells to detect invading pathogens[225]. Furthermore, LL-37 promotes the expression of chemokines including CXCL8/IL-8, monocyte chemoattractant protein-1 (MCP-1) and monocyte chemoattractant protein-3 (MCP-3) by activating ERK1/2 and p38 in human blood derived monocytes, and induces chemotaxis, proliferation and differentiation of monocytes[226].
Similarly, defensins have a potent pro-inflammatory function[202]. Human α-defensins mainly consist of human neutrophil peptide (HNP) 1–4 and human defensin (HD) 5–6, and β-defensins mainly consist of HBD1-4. These AMPs are widely found in immune cells such as neutrophils, monocytes/macrophages, lymphocytes, NK cells and Paneth cells[202,227-229]. HNP1-3 causes the release of TNF-α and IFN-γ from macrophages and acts in an autocrine manner to increase the expression of CD32 (FcγRIIB) and CD64 (FcγRI), and thereby enhance phagocytosis of macrophages[230]. HBDs regulate the activity of a wide range of immune cells, including monocytes/macrophages, DCs, memory T cells and mast cells[202,219]. Niyonsaba et al.[231] found that HBD2-4 rather than HBD1 could stimulate the expression of IL-6, IL-10, IFN-γ-inducible protein IP-10, MCP-1, macrophage inflammatory protein-3α (MIP-3α) and RANTES/CCL5 in human keratinocytes. HBD2 and HBD3 stimulate the mononuclear and polymorphonuclear cells to produce TNF-α, IL-10 and IL-6 in an inflammatory environment, while HNP1 stimulates the mononuclear cells to produce IFN-γ, IL-10 and IL-6[232]. Besides, these cytokines in turn promote immune cells to express more AMPs[233]. Porcine β-defensin 2 protects against bacterial infection through direct bactericide action and altered inflammation by interfering with the TLR4/NF-κB pathway and inhibiting the release of pro-inflammatory cytokines, including IL-6, TNF-α, IL-1β and IL-12[234]. Sechet et al.[235] found that the small molecules isolated from medicinal plants, andrographolide, oridonin, and isoliquiritigenin, induced the expression of HBD3 in colon epithelial cells by targeting the epidermal growth factor receptor (EGFR)/MAPK pathway.
On the other hand, the affinity of AMPs to pathogen may facilitate infection under certain situations. By targeting human enteric HD5, Shigella infects intestinal epithelium through the interaction between bacterial surface proteins and HD5 to enhance adhesion and invasion of intestinal epithelium[236]. Interestingly, HD5 in macrophage can also promote the phagocytosis of Shigella and the bacterial replication causes macrophage cell death and the subsequent release of bacteria to infect the intestinal epithelial cells[237].
While appropriate inflammatory responses accelerate the removal of invading pathogens and infected cells, the excessive and long-term inflammation can lead to tissue damage, chronic inflammatory disease which contributes to oncogenic transformation. Therefore, when the degree of inflammation reaches a certain level, the inflammatory response should be controlled to maintain microenvironment homeostasis. AMPs have either pro-inflammatory or anti-inflammatory effects according to their expression levels in the sites of inflammation[238].
Hosoda et al.[239] found that LL-37 not only released NETs to inhibit the growth of bacteria, but also improved the survival of cecal ligation and puncture (CLP) sepsis mice by alleviating inflammatory responses through reducing cytokines, soluble TREM-1 and danger-associated molecular patterns (DAMPs). Furthermore, LL-37 mediates the internalization of the chemokine receptor CXCR2 in the monocytes and neutrophils and subsequently attenuates their chemotaxis[240]. LL-37 also significantly reduces the release of pro-inflammatory cytokines in LPS-stimulated neutrophils while inducing the production of intracellular ROS and the intracellular ingestion of bacteria[241]. In addition, LL-37 suppresses Aspergillus fumigatus infection by binding the fungal hyphae, and reduces the release of pro-inflammatory cytokines by macrophages[242]. Therefore, AMPs exert immunomodulatory effect to prevent infection-associated tissue damages and maintain microenvironment homeostasis.
Tumor modulatory activity
Growing evidence supports an anticancer activity of AMPs[3,243]. AMPs selectively kill cancer cells by acting on the membrane surface. Compared with normal cells, the anionic composition of cancer cells’ membrane surface confers the targeting specificity of AMPs. Paradoxically, AMPs can promote tumor progression in the certain types of cancer. Thus, the functional role of AMPs in cancer cells is tumor type specific[244] (Fig. 3).
LL-37, the only cathelicidin in humans, inhibits tumor growth in colon cancer[245-247] and gastric cancer. LL-37 induces apoptosis-inducing factor (AIF)/endonuclease G (EndoG) mediated apoptosis by activating the GPCR-p53-Bax/Bak/Bcl-2 signaling cascade in colon cancer cells. Cathelicidin-deficient mice showed a higher sensitivity to azoxymethane-induced colon cancer occurrence[248]. Cathelicidin has been reported to inhibit colon tumor growth and metastasis through P2RX7-dependent pathways in mice[249]. Hayashi et al.[250] found that FF/CAP18, an analog of LL-37, was localized to the cytoplasm of colon cancer cells and enhanced the expression of growth-suppressing miRNAs. These miRNAs were also transported to other cancer cells via exosomes to inhibit proliferation. In gastric cancer, the abundance of LL-37 is lower than in normal tissues[247]. LL-37 activates bone morphogenetic protein (BMP) signaling through a proteasome-dependent mechanism to inhibit gastric cancer cell proliferation[251]. In addition, other AMPs including KT2[252,253], BG-4[254] and KL15[255] induce apoptotic or necrotic cancer cell death.
Paradoxically, LL-37 promotes tumorigenesis in breast cancer, ovarian cancer, malignant melanoma, lung cancer, prostate cancer, pancreatic cancer and squamous cell carcinoma of the skin[256]. For instance, LL-37 was found to be highly expressed in breast cancer[257], and promoted the migration and metastasis of breast cancer cells[258]. In ovarian cancer, it enhances the proliferation, migration and invasion of ovarian cancer cells[247]. This pro-tumorigenic effect of LL-37 is associated with the immune modulation. Ovarian cancer cells produce versican V1 which induces the production of LL-37 by activating macrophage TLR2 and vitamin D3 signals. LL-37 promotes ovarian tumor growth by recruiting multipotent mesenchymal stromal cells[259]. LL-37 also promotes the proliferation, migration and invasion of melanoma cells by activating the NF-κB pathway[260], and promotes the growth of lung cancer through the Wnt/β-catenin and MAPK signaling pathways[261]. A recent research found that LL-37 secreted by tumors may be used as an immunosuppressive cytokine to induce tumor immune tolerance by converting effector Th17 cells into suppressor Th17 cells[262].
Like cathelicidins, defensins act as a double edge sword in the development of cancer pathogenesis. High concentrations of HNP1, HNP2 and HNP3 (HNP1-3) were found to be positively correlated with cell necrosis in renal cell carcinoma (RCC) tissues[263]. A significantly increased level of HNP1-3 was also detected in cancer tissues and serum of patients with metastatic colorectal cancer[264]. Similar to HNP1-3, a high level of HD6 was detected in colon cancer tissues and colon cancer cell lines[265], supporting a potential prognostic value of HNP1-3 and HD6 in colorectal cancer. On the other hand, the anti-tumor activity of HNP1-3 has been reported in some types of tumors. HNP1 inhibits tumor growth in lung adenocarcinoma[266], colon and breast tumors by inducing apoptosis, reducing angiogenesis and mediating anti-tumor immunity[267]. It also significantly improves the efficacy of doxorubicin in breast cancer and lactoferrin in oral squamous cell carcinoma (OSCC)[268]. Moreover, HNP1-3 derived from neutrophils have cytotoxic effects on OSCC cells[269].
As another major class of defensins in humans, low expression levels of HBD1, HBD2 and HBD3 had been reported in colon cancer[207,270] and OSCC[271,272], while one study showed increased expression of HBD2 in OSCC[273]. This apparent contradiction may be explained by the level of inflammation in the biopsy section[272]. The low protein expression of HBD1 has been detected in 82% of prostate cancer, 90% of RCC and liver cancer[274-276]. The oncogenic EGFR-ERK-MYC signal axis suppressed the expression of HBD1 in colon cancer[277]. Overexpression of HBD1 leads to caspase-3-mediated apoptosis in renal cancer cells SW156 and epidermoid carcinoma cells[275]. HBD1 also inhibits the growth of bladder cancer through the HER2-ERK pathway[278,279]. Like HBD1, the low expression of HBD2 has been reported in oral tongue squamous cell carcinoma[280]. Its tumor inhibitory effect on colon tumor is through anti-tumor immunity[281]. This immune modulatory effect was further demonstrated that infection with a recombinant VV expressing HBD2 led to recruitment of the plasmacytoid DCs to the tumor sites, enhancing cytotoxic T cells to attack tumor cells, thereby inhibiting tumor growth[282]. HBD3 also inhibits the migration of head and neck cancer cells[283], and the growth of lung cancer[284]. The HBD3 produced by tumor-infiltrating neutrophils inhibited the migration of colon cancer cells through metastasis-related 1 family member 2 in a paracrine manner[207]. On the other hand, an oncogenic role of HBD3 has been suggested in cervical cancer by activating NF-κB signaling[285], and in head and neck squamous cell carcinomas (HNSCC) by inducing the expression of programmed death-ligand 1 (PD-L1)[286].
θ-defensin derivatives specifically inhibit the proliferation of breast cancer cells but spare normal breast epidermal cells[287]. Homozygous deletion of the θ-defensin gene in different cancers activates oncogenic pathways and suppresses immune response pathways[288], implicating its potential as a prognostic biomarker for immunotherapy. Treatment with the plant-derived natural defensin PvD1 in breast cancer cells inhibits tumor growth by modulating the exosomal membrane composition[289]. A novel frog skin-isolated peptide dermaseptin-PP exerts the anti-tumor activity in lung cancer cells by inducing cell apoptosis via both endogenous mitochondrial apoptosis pathway and exogenous death receptor apoptosis pathway[290]. PFR peptide induces necroptosis of acute myeloid leukemia cells by inducing endoplasmic reticulum stress and mitochondrial oxidative stress[171]. The diverse roles of other AMPs in cancer have been summarized in Additional file 1: Table S2.
Other activities
AMPs can promote wound healing[291-293] after skin injury, a process involving the complex interactions of keratinocytes, fibroblasts, vascular endothelial cells, immune cells and the extracellular matrix[294-296]. Some AMPs play a vital role in both skin barrier and function[297] and thus have the potential to treat multiple skin maladies, exemplified by melanoma, acne, diabetic foot ulcer and psoriasis[298]. Experimental studies revealed that LL-37[299] and S100 peptide[300] in keloid tissues mitigated collagen production, supporting the AMPs’ anti-fibrogenic properties. Yan et al.[301] recently reported that the anti-fibrotic properties of AMP YD were mediated through the miR-155/ Casp12/NF-kB pathway. In addition, the recombinant LL-37 can induce endothelial cell proliferation, migration and formation of tubule-like structures, and increase vascularization and re-epithelialization in mouse trauma experiments[302]. AMPs are related to the occurrence and development of diabetes[303,304]. In patients with type 2 diabetes, the level of LL-37 in serum was found to be positively correlated with inflammation markers and negatively correlated with the level of high-density lipoprotein (HDL)[305]. Under the influence of short-chain fatty acids produced by intestinal microorganisms, cathelicidin related antimicrobial peptide (CRAMP) produced by pancreatic β-cells induces activation of the regulatory immune cells and thereby reducing the incidence of autoimmune diabetes[306].
AMPs can regulate NETs and inflammation and are involved in the process of sepsis infection. LL-37 improved the survival of polybacterial septic mice by neutralizing the effects of LPS and inhibiting ATP-induced/P2X7-mediated pyroptosis of macrophage, a caspase-1 dependent cell death and inflammatory cytokine production[307,308]. In addition, AMPs play a vital role in maintaining colon homeostasis, tissue repair and preventing cancer by maintaining the balance of colon microbiota[309–311].
Strategies of AMPs for clinical application and development
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The inappropriate and excessive use of antibiotic leads to antibiotic resistance, a major clinical challenge. AMPs with a broad-spectrum antibacterial activity are expected to become the alternative antibiotics through the development of AMPs-based therapies. Currently, three AMPs have been approved for antibacterial treatment by the Food and Drug Administration (FDA) and another three AMPs are under the clinical development (Additional file 1: Table S3).
Cancer patients are often accompanied by an inflammatory response and the risk of postoperative pathogen infection. The antibiotic resistance has a significant impact on cancer patient survival. The immunomodulatory function and the direct anti-tumor activity make AMP-based therapies as an attractive treatment option for cancer patients. Three AMPs have been tested in the clinical trials for cancer treatment (Additional file 1: Table S3). To support the value of AMP in cancer treatment, a study recently demonstrated that tumor samples contained abundant microbiome[312]. Conventional antibiotics alone may not effectively eliminate the bacteria in tumor cells. Therefore, as both the anticancer peptides and antibacterial agents, AMPs open a new perspective for the treatment of cancer.
However, development of AMP-based therapy has encountered many challenges including stability, efficacy and toxicity, which limit the clinical development of AMPs. Particularly the undesirable pharmacodynamics of AMPs including the instability of AMPs resulting from the degradation of AMPs by the presence of proteolytic enzymes in the serum[313]; the neutralization of AMPs antitumor activities by the negatively charged proteins and high/low density lipoproteins[314]; and the rapid clearance by kidney and liver[315], their therapeutic applications. Therefore, new technologies should be exploited to improve the bioavailability of AMPs.
Rational engineering of AMPs
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Novel technologies can be applied for AMP engineering to improve their stability, activity and targetability, such as isomerization, peptide lipidation, glycosylation, cyclization, other biomimetic terminal modification and multimerization[316-318]. The activity of AMPs is influenced by many factors, such as peptide length, net charge, hydrophobicity and secondary structure. The antimicrobial activity is varied by the peptide length because peptides need to span the lipid bilayer in order to stabilize the pore[319]. But with the change of the peptide length, the net positive charge and hydrophobicity are also changed. The increased AMP positive charge results in an enhanced peptide binding to the anionic bacterial membranes[320]. However, the biological effect of highly charged peptides is significantly reduced at high ionic strength[319]. In the presence of hydrophobic groups, peptide chains can form polymers in solution which enable peptides to insert into the hydrophobic membrane core. Hydrophobic residues also increase the ability of the AMPs to form α-helix and the stability. When the AMPs form a certain secondary structure, it shows obvious amphiphilicity. The amphiphilicity is an important structural basis of AMPs. However, some studies have shown that high amphiphilicity decreased the antibacterial activity of AMPs, and led to an increase of hemolytic activity[321,322]. For these reasons, there is no standard solution to optimize AMP engineering with coordinating various factors simultaneously.
L-to-D isomerization is a common method that enhances the proteolytic stability of peptide against a range of host and microbes’ proteases. L-amino acids are easily degraded. In order to increase their stability in serum, cyclization of AMPs, the addition of unnatural amino acids and D-amino acids are often used to modify AMPs[323-325]. For instance, chicken cathelicidin-2 after D-amino acid substitution and head-to-tail cyclization, showed enhanced serum stability and reduced cytotoxicity without affecting antibacterial and LPS neutralizing activity[324]. D-Arg-W3R6, an analogue of AMP W3R6 after partial D-amino acid substitution, showed increasing resistance to proteolytic enzymes without changing its antibacterial activity[326]. The mammalian HBcARD peptide after D-amino acid substitution also showed better stability, stronger antibacterial activity and very low hemolytic activity[327]. The di-substituted β-amino acids within the peptide enhance the stability, lipophilicity and ability of AMPs to penetrate target cells[328]. In addition, AMPs, linker and targeting peptide can be connected by the peptide bonds to form specifically targeted antimicrobial peptides (STAMP). The linker containing L-type or D-type amino acid enantiomers increases the stability and activity of AMP or the targeting peptide[329].
Cyclization of peptides is a particularly promising approach for improving both stability and bioactivity of AMPs[330]. Cyclic peptides bind strongly to bacterial membrane by forming a β-sheet structure at the membrane surface[331]. Dathe et al.[332] designed a series of short cyclic hexapeptides that possessed a higher antimicrobial efficacy against Bacillus subtilis and E. coli than compared to the linear form. A recent study reported that the analogues of a cyclic AMP with a flexible linker exhibited improved activity against S. aureus and P. aeruginosa compared to the original linear peptide[333]. Another form of cyclization is to rely on the disulfide bond formation to create the intramolecular cross-link between cysteine residues, which enhances proteolytic stability[334].
Stapling is a key technique of forcing peptides structure into an α-helical by the linkage of the side chains[335]. A very recent report from Demizu’s group designed and synthesized magainin 2 derivatives by stapling between the first and fifth position from the N-terminus, which showed a higher antimicrobial activity against both Gram-positive and Gram-negative bacteria than magainin 2, without exerting significant hemolytic activity[336].
The combination of two AMPs was reported to produce a stronger activity against bacteria[337]. However, the issue of host toxicity remains unresolved. Later, a more attractive hybridization strategy was proposed that the new synthesized AMP involves the combination of key residues from 2 to 3 peptides of different mechanisms of actions into a single sequence[338,339]. The group of Alzoubi designed a new hybrid peptide H4 by combining two individual α-helical fragments of both BMAP-27 and OP-145, which displayed a broad spectrum of activity and reduced the toxicity profiles[338]. In another study, the “triple hybrid” of cecropin-A, melittin, and LL-37 significantly enhanced the bactericidal against a range of Gram-positive and Gram-negative organisms and lowered hemolytic activity[340]. Antibiotics-peptide conjugates (APCs) are a combination of known antibiotics with a peptide connected through a linker. The rationale is to produce an alternative multifunctional antimicrobial compound that will elicit synergistic antibacterial activities while reducing known shortcomings of antibiotics or peptides, such as cellular penetration, serum instability, cytotoxicity, hemolysis and instability in high salt conditions[341].
AMPs have the ability to self-assemble into an ordered amyloid-like nanostructures which facilitate their antibacterial activity by achieving more specific and stronger interactions with microbial membranes[342]. Nanomaterials can effectively kill bacteria by destroying bacterial cell membrane and causing intracellular material leakage. During membrane penetration, nanomaterials can bind to many components in bacterial cells, such as DNA, ribosomes and enzymes, and disrupt normal physiological activities of the cell, resulting in the oxidative stress, electrolyte imbalance, enzyme inhibition and other bacteriostatic effects, and ultimately lead to cell death[343].
Delivery system
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Some AMPs not only inhibit the growth of tumor cells, but also have cytotoxicity to normal cells[314]. This non-specificity is a major obstacle for successful AMP-based therapy[344]. In order to achieve tumor specific targeting, vector-mediated gene delivery AMPs has been proposed.
The nanotechnology provides stability and controlled release of AMPs to increase target selectivity. Nanostructure can improve pharmacodynamics of AMPs by inhibiting renal clearance and enhancing retention and permeability[345]. Some nanomaterials not only can enhance the stability and activity of AMPs but also have antibacterial effects[346]. Nano-delivery systems can optimize the pharmacokinetics and biodistribution of AMP, and improve biosafety and antibacterial effectiveness[347]. The types of nanostructures used in AMP delivery systems include metal nanoparticles, carbon nanotubes, lipid-based nanoparticles and polymerbased nanostructures[345]. Lam et al.[348] synthesized structurally nanoengineered antimicrobial peptide polymers (SNAPPs) by α-amino acid N-carboxyanhydrides (NCAs)-ring-opening polymerization (ROP), and exhibited sub-μM activity against all Gram-negative bacteria tested, and demonstrated low toxicity. It was reported that a new nanosystem that the encapsulation of SETM33 peptide in single-chain dextran nanoparticles markedly inhibited P. aeruginosa infections[349]. In addition, generation of AMP-magnetic nanoparticles has been proposed to increase target specificity by immobilizing AMP on the surface of magnetic nanoparticles and applying an external magnetic field to control its delivery[350]. A new class of three-dimensional nanostructures, tetrahedral framework nucleic acids (tFNAs), also possesses a desirable cell-entry performance and has been utilized as a delivery vehicle[351]. In recent years, a significant progress has been achieved in the field of using nanosystems to transform or deliver AMPs, making AMPs truly an effective substitute for antibiotic therapy[347,352-355]. However, as drug delivery systems, there are still several key issues around the drug delivery systems such as biocompatibility and nanoparticles deposition[356,357].
Cell-penetrating peptides (CPPs) are efficient vehicles that can deliver various cargos across the biological membranes to maximize their intracellular activities[358]. Thus, fusing AMPs with CPPs could be a simple and feasible method to improve the bioactivity of AMPs. Accumulating evidences support the generation of cell-penetrating antimicrobial peptides as a new perspective for targeting intracellular infections[359]. As Lee et al.[360] elegantly showed conjugated CPP (R9) to AMPs (magainin and M15) significantly enhanced antimicrobial activity against Gram-negative bacteria, probably due to an increased efficiency of translocating across a lipid bilayer. Another example of CPP-AMP conjugation was reported by Hoffmann’s group through coupling the PrAMPs with penetratin (residues 43 to 58 in the antennapedia homeodomain) via their C-terminally adding cysteine to shut into mammalian cells[361]. Both AMPs and CPPs are membrane-active peptides because of the similar action on membranes and the common physicochemical characteristics. The latarcin derived peptide (LDP)-nuclear localization sequence (NLS) derived CPPs is a dual action peptide with AMP and CPP activity[362]. Drexelius et al.[363] recently reported the optimization of a CPPs C18 towards its antimicrobial activity. Surprisingly, the peptide has not only antibacterial activity but also specific antitumor activity. Therefore, connection of peptides with CPPs can increase the therapeutic efficacy and specificity of AMPs in cancer treatment. Hao et al.[364] used the TAT protein of the HIV virus as a CPP, then combined this CPP with the amphiphilic α-helical anti-cancer peptide (ACP). The CPP-ACP complex showed a potent inhibitory effect on the growth of cancer cells, and reduced the toxicity on human erythrocytes.
Drug combination
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Antibiotics in combination with AMPs is a potential therapeutic approach to overcome the antibiotic resistance, improve the killing effect and reduce concentration-associated toxicity or side effects of antibiotics. This strategy can increase the bacterial membrane permeability, decrease the efflux of antibiotic agents, affect intracellular ion homeostasis, and thus, inhibit biofilm formation and bacterial survival[365].
Several AMPs, HsAFP1, RsAFP2 and RsAFP1, showed a synergistic activity with the antimicrobial agents in treating both plankton and biofilm cells[366]. Nisin combined with the antibiotics, such as penicillin, chloramphenicol, ciprofloxacin, indolicidin, or azithromycin, showed the synergistic effect on methicillin-resistant S. aureus by preventing biofilm formation or inhibiting attachment of bacteria to solid surface[367,368]. Li et al.[369] demonstrated that combination of tetracycline antibiotics demeclocycline hydrochloride (DMCT) and the antimicrobial peptide SAAP-148 has a synergistic antibacterial activity to combat multidrug-resistant (MDR) P. aeruginosa strains PAO1 and P. aeruginosa ATCC27853. The liver-expressed antimicrobial peptide 2 (LEAP-2), which derived from fish innate immune system, increased the activity of ampicillin against Vibrio parahaemolyticus, thus overcoming ampicillin-resistant Aeromonas hydrophila infection[370]. In addition to LL-37 from humans[371], Xenopus laevis antibacterial peptide-P2 from Xenopus laevis[151] and HsAFP1 from plant[372] in combination with the antibiotics effectively control bacterial or fungal infection. Casciaro et al.[373] also found that esculentin-1a derived antipseudomonal peptides from frog-skin had the ability to improve the activity of aztreonam in inhibiting growth and killing pseudomonas cells.
A combination of two or more types of AMPs can also achieve better efficacy. However, only a few examples of synergistic AMPs have been reported[374], including PGLa and magainin 2, which are two amphiphilic α-helical membranolytic peptides from frog skin and belong to the magainin family[375]. The team of Ulrichy proposed a new molecular model for the functionally active PGLa-magainin 2 complex in which each PGLa monomer bound to one magainin 2 molecule at its C-terminus[376]. Ma et al.[377] found that while PGLa inserted into and extracted from a membrane rapidly whereas magainin 2 tended to aggregate on the membrane surface, formation of the PGLa-magainin 2 heterodimers enabled the PGLa and MAG2 residues to be well integrated into the membrane. The combination of magainin 2 and tachyplesin 1 also enhances the bacterial membrane recognition by constituting the oligomeric structures before contacting the anionic bacterial membrane surface[378]. In addition, a recent study from Bhunia’s group reported that two AMPs, VG16KRKP and KYE28, exhibited synergistic antimicrobial effects against plant pathogens and proteases through formatting an unusual peptide complex[379].
The synergistic antimicrobial effects can also be achieved by combining AMPs with other compounds or drugs. A better antibacterial activity of nisin combined with citric acid against S. aureus and L. monocytogenes resulted from a stronger damage to the cell morphology and greater release of cell constituents[380]. Ahn et al.[381] showed that the C-terminal 15 amino acids of HBD3-C15 potentiated the bactericidal and anti-biofilm activity of disinfectants used in dental clinics against Streptococcus mutans, as well as calcium hydroxide and chlorhexidine digluconate. The treatment with nisin A and epsilon-poly-L-lysine showed a synergistic activity against Gram-positive food-borne pathogens Bacillus cereus and L. monocytogenes[382]. Notably, the development of the synthetic antimicrobial polymers driven by the advance of controlled polymerization techniques and the desire to mimic AMPs is an innovative approach to combating the increasing prevalence of MDR infections[383]. The bactericidal activity can be further increased by the different combination therapies involving synthetic antimicrobial polymers[348,383-385].
Conclusions
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Taken together, AMPs have a broad-spectrum anti-pathogenic activity, as well as powerful immune regulation and anti-cancer properties. AMPs have a strong cell killing effect on MDR bacteria and cancer cells. Therefore, AMPs offer a promising revenue to address the problem of antibiotic resistance and chemotherapy resistance of cancer cells. On the other hand, their shortcomings, such as poor stability, toxicity and other side effects, may limit the clinical development. The emergence of new technologies allows us to transform the natural AMPs and synthesize new AMPs by effectively exploiting the desirable characteristics, such as amphiphilicity and lipophilicity. Furthermore, the combination strategies with AMPs holds the potential to reduce the toxicity and side effects and prevent drug resistance. Although a few AMPs have already been approved by the FDA or are in the late stages of clinical trials, the exploration road ahead is still long. We are looking forward to developing the AMP-based treatment strategies with improved safety, specificity and efficacy for bacterial infection and cancer therapy in the future.
Abbreviations
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ACP: Anti-cancer peptide; APCs: Antibiotics-peptide conjugates; AIF: Apoptosis-inducing factor; AMPs: Antimicrobial peptides; ATCUN: Amino terminal copper and nickel; BMP: Bone morphogenetic protein; C. albicans: Candida albicans; CL: Cardiolipin; CLP: Cecal ligation and puncture; CpG-ODN: CpG oligodeoxynucleotides; CPPs: Cell-penetrating peptides; CRAMP: Cathelicidin related antimicrobial peptide; DAMPs: Danger-associated molecular patterns; DBAASP: Database of Antimicrobial Activity and Structure of Peptides; DCs: Dendritic cells; DENV: Dengue virus; DMCT: Demeclocycline hydrochloride; DPG: Diphosphatidylglycerol; EGFR: Epidermal growth factor receptor; E. coli: Escherichia coli; E. faecalis: Enterococcus faecalis; EMT: Epithelial-mesenchymal transition; EndoG: Endonuclease G; ERK1/2: Extracellular signal-regulated kinase 1/2; FDA: Food and Drug Administration; FoxO: Forkhead box transcription factor O; FPRs: Formyl peptide receptors; GPCR: G-protein coupled receptor; HBD: Human β-defensin; HD: Human defensin; HDL: High-density lipoprotein; HIV: Human immunodeficiency virus; HLH: Helix-loop-helix; HNP: Human neutrophil peptide; HNSCC: Head and neck squamous cell carcinomas; HSV: Herpes simplex virus; IAV: Influenza A virus; IFNs: Interferons; JNK: JUN N-terminal kinase; LEAP-2: Liver-expressed antimicrobial peptide 2; LDP: Latarcin derived peptide; L. monocytogenes: Listeria monocytogenes; LPS: Lipopolysaccharide; MAPK: Mitogen-activated protein kinase; MCP-1: Monocyte chemoattractant protein-1; MDR: Multidrug-resistant; MIC: Minimal inhibitory concentration; MIP-3α: Macrophage inflammatory protein-3α; MrgX2: Mas-related gene X2; NCAs: N-carboxyanhydrides; NETs: Neutrophil extracellular traps; NF-κB: Nuclear factor-κB; NKs: Natural killer cells; NLS: Nuclear localization sequence; OSCC: Oral squamous cell carcinoma; P. aeruginosa: Pseudomonas aeruginosa; PC: Phosphatidylcholine; PD-L1: Programmed death-ligand 1; PE: Phosphatidyl ethanolamine; PG: Phosphatidylglycerol; PI: Phosphatidylinositol; PI3K: Phosphoinositide 3-kinase; PrAMPs: Proline-rich AMPs; PS: Phospholipids such as phosphatidylserine; RCC: Renal cell carcinoma; RF: Release factor; ROP: Ring-opening polymerization; ROS: Reactive oxygen species; S. aureus: Staphylococcus aureus; SAAP: Surfactant associated anion peptide; SDS: Sodium dodecyl sulfate; SNAPPs: Structurally nanoengineered antimicrobial peptide polymers; STAMP: Specifically targeted antimicrobial peptide; TAFs: Tumor-associated fibroblasts; TBD-1: Turtle β-defensin 1; tFNAs: Tetrahedral framework nucleic acids; TLRs: Toll-like receptors; TNFs: Tumor necrosis factors; VV: Vaccinia virus; ZIKV: Zika virus.
Supplementary information
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The online version contains supplementary material available at https://doi.org/10.1186/s40779-021-00343-2.
Additional file 1. Table S1. Structure and characteristics of AMPs. Table S2. The mechanism of anti-cancer activity of AMPs. Table S3. Selected AMPs in clinical phase of development.
Acknowledgements
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Not applicable.
Authors’ contributions
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QYZ, ZBY, YMM and XYH were involved in drafting the manuscript, reviewed the manuscript; GS edited the manuscript; JJM and XRC collected the data; JL and JK reviewed the literature; CYF conceived and supervised the study. All authors read and approved the final manuscript.
Availability of data and materials
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Not applicable.
Declarations
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Ethics approval and consent to participate
Not applicable.
Consent for publication
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Not applicable.
Competing interests
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The authors declare that they have no competing interests.
Author details
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1Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou 310018, China. 2Department of Oncology, The 903rd Hospital of PLA, Hangzhou 310013, China. 3Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd. South, San Francisco, CA 94158, USA. 4Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia. 5Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
Funding
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  • grants from the National Natural Science Foundation of China(81770176)
  • special support plan for Zhejiang Province High-Level Talents(2019R52011)
References
Less
1.
Wang J, Dou X, Song J, Lyu Y, Zhu X, Xu L, et al. Antimicrobial peptides: promising alternatives in the post feeding antibiotic era. Med Res Rev. 2019;39(3):831-59.
2.
Mohammed I, Said DG, Dua HS. Human antimicrobial peptides in ocular surface defense. Prog Retin Eye Res. 2017;61:1-22.
3.
Kang HK, Kim C, Seo CH, Park Y. The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J Microbiol. 2017;55(1):1-12.
4.
Lei J, Sun L, Huang S, Zhu C, Li P, He J, et al. The antimicrobial peptides and their potential clinical applications. Am J Transl Res. 2019;11(7):3919-31.
5.
Kang X, Dong F, Shi C, Liu S, Sun J, Chen J, et al. DRAMP 2.0, an updated data repository of antimicrobial peptides. Sci Data. 2019;6(1):148.
6.
Mookherjee N, Anderson MA, Haagsman HP, Davidson DJ. Antimicrobial host defence peptides: functions and clinical potential. Nat Rev Drug Discov. 2020;19(5):311-32.
7.
Roudi R, Syn NL, Roudbary M. Antimicrobial peptides as biologic and immunotherapeutic agents against cancer: a comprehensive overview. Front Immunol. 2017;8:1320.
8.
Zhang LJ, Gallo RL. Antimicrobial peptides. Curr Biol. 2016;26(1):R14-9.
9.
Pfalzgraff A, Brandenburg K, Weindl G. Antimicrobial peptides and their therapeutic potential for bacterial skin infections and wounds. Front Pharmacol. 2018;9:281.
10.
Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol Spectr. 2016. https://doi.org/10.1128/microbiolspec.VMBF-0016-2015.
11.
Hiltunen T, Virta M, Laine AL. Antibiotic resistance in the wild: an eco-evolutionary perspective. Philos Trans R Soc Lond B Biol Sci. 2017;372(1712):20160039.
12.
Chung PY, Khanum R. Antimicrobial peptides as potential anti-biofilm agents against multidrug-resistant bacteria. J Microbiol Immunol Infect. 2017;50(4):405-10.
13.
Mwangi J, Hao X, Lai R, Zhang ZY. Antimicrobial peptides: new hope in the war against multidrug resistance. Zool Res. 2019;40(6):488-505.
14.
Costa F, Teixeira C, Gomes P, Martins MCL. Clinical application of AMPs. Adv Exp Med Biol. 2019;1117:281-98.
15.
Mahlapuu M, Håkansson J, Ringstad L, Björn C. Antimicrobial peptides: an emerging category of therapeutic agents. Front Cell Infect Microbiol. 2016;6:194.
16.
Groisman EA. How bacteria resist killing by host-defense peptides. Trends Microbiol. 1994;2(11):444-9.
17.
Yazici A, Ortucu S, Taskin M, Marinelli L. Natural-based antibiofilm and antimicrobial peptides from microorganisms. Curr Top Med Chem. 2018;18(24):2102-7.
18.
Moyer TB, Heil LR, Kirkpatrick CL, Goldfarb D, Lefever WA, Parsley NC, et al. PepSAVI-MS reveals a proline-rich antimicrobial peptide in Amaranthus tricolor. J Nat Prod. 2019;82(10):2744-53.
19.
Lee JH, Seo M, Lee HJ, Baek M, Kim IW, Kim SY, et al. Anti-inflammatory activity of antimicrobial peptide allomyrinasin derived from the Dynastid Beetle, Allomyrina dichotoma. J Microbiol Biotechnol. 2019;29(5):687-95.
20.
Kim SY, Zhang F, Gong W, Chen K, Xia K, Liu F, et al. Copper regulates the interactions of antimicrobial piscidin peptides from fish mast cells with formyl peptide receptors and heparin. J Biol Chem. 2018;293(40):15381-96.
21.
Li B, Lyu P, Xie S, Qin H, Pu W, Xu H, et al. LFB: a novel antimicrobial brevinin-like peptide from the skin secretion of the Fujian Large Headed Frog, Limnonectes fujianensi. Biomolecules. 2019;9(6):242.
22.
van Hoek ML, Prickett MD, Settlage RE, Kang L, Michalak P, Vliet KA, et al. The Komodo dragon (Varanus komodoensis) genome and identification of innate immunity genes and clusters. BMC Genomics. 2019;20(1):684.
23.
Braun MS, Sporer F, Zimmermann S, Wink M. Birds, feather-degrading bacteria and preen glands: the antimicrobial activity of preen gland secretions from turkeys (Meleagris gallopavo) is amplified by keratinase. FEMS Microbiol Ecol. 2018. https://doi.org/10.1093/femsec/fiy117.
24.
Wang X, Sun Y, Wang F, You L, Cao Y, Tang R, et al. A novel endogenous antimicrobial peptide CAMP211-225 derived from casein in human milk. Food Funct. 2020;11(3):2291-8.
25.
Mattick AT, Hirsch A. Further observations on an inhibitory substance (nisin) from lactic streptococci. Lancet. 1947;2(6462):5-8.
26.
Gharsallaoui A, Oulahal N, Joly C, Degraeve P. Nisin as a food preservative: part 1: physicochemical properties, antimicrobial activity, and main uses. Crit Rev Food Sci Nutr. 2016;56(8):1262-74.
27.
Shin JM, Gwak JW, Kamarajan P, Fenno JC, Rickard AH, Kapila YL. Biomedical applications of nisin. J Appl Microbiol. 2016;120(6):1449-65.
28.
Kitagawa N, Otani T, Inai T. Nisin, a food preservative produced by Lactococcus lactis, affects the localization pattern of intermediate filament protein in HaCaT cells. Anat Sci Int. 2019;94(2):163-71.
29.
Alkotaini B, Anuar N, Kadhum AAH, Sani AA. Detection of secreted antimicrobial peptides isolated from cell-free culture supernatant of Paenibacillus alvei AN5. J Ind Microbiol Biotechnol. 2013;40(6):571-9.
30.
Yi T, Huang Y, Chen Y. Production of an antimicrobial peptide AN5-1 in Escherichia coli and its dual mechanisms against bacteria. Chem Biol Drug Des. 2015;85(5):598-607.
31.
Garcia-Gutierrez E, Mayer MJ, Cotter PD, Narbad A. Gut microbiota as a source of novel antimicrobials. Gut Microbes. 2019;10(1):1-21.
32.
Pushpanathan P, Mathew GS, Selvarajan S, Seshadri KG, Srikanth P. Gut microbiota and its mysteries. Indian J Med Microbiol. 2019;37(2):268-77.
33.
Essig A, Hofmann D, Münch D, Gayathri S, Kunzler M, Kallio PT, et al. Copsin, a novel peptide-based fungal antibiotic interfering with the peptidoglycan synthesis. J Biol Chem. 2014;289(50):34953-64.
34.
Srivastava S, Dashora K, Ameta KL, Singh NP, El-Enshasy HA, Pagano MC, et al. Cysteine-rich antimicrobial peptides from plants: the future of antimicrobial therapy. Phytother Res. 2021;35(1):256-77.
35.
Höng K, Austerlitz T, Bohlmann T, Bohlmann H. The thionin family of antimicrobial peptides. PLoS ONE. 2021;16(7):e0254549.
36.
Li J, Hu S, Jian W, Xie C, Yang X. Plant antimicrobial peptides: structures, functions, and applications. Bot Stud. 2021;62(1):5.
37.
Taveira GB, Mello EO, Souza SB, Monteiro RM, Ramos AC, Carvalho AO, et al. Programmed cell death in yeast by thionin-like peptide from Capsicum annuum fruits involving activation of caspases and extracellular H+ flux. Biosci Rep. 2018;38(2):BSR20180119.
38.
Hao G, Bakker MG, Kim HS. Enhanced resistance to Fusarium graminearum in transgenic arabidopsis plants expressing a modified plant thionin. Phytopathology. 2020;110(5):1056-66.
39.
Tang SS, Prodhan ZH, Biswas SK, Le CF, Sekaran SD. Antimicrobial peptides from different plant sources: isolation, characterisation, and purification. Phytochemistry. 2018;154:94-105.
40.
Gourbal B, Pinaud S, Beckers GJM, Van Der Meer JWM, Conrath U, Netea MG. Innate immune memory: an evolutionary perspective. Immunol Rev. 2018;283(1):21-40.
41.
Wu Q, Patočka J, Kuča K. Insect antimicrobial peptides, a mini review. Toxins (Basel). 2018;10(11):461.
42.
Loch G, Zinke I, Mori T, Carrera P, Schroer J, Takeyama H, et al. Antimicrobial peptides extend lifespan in Drosophila. PLoS ONE. 2017;12(5):e0176689.
43.
Hanson MA, Lemaitre B. New insights on Drosophila antimicrobial peptide function in host defense and beyond. Curr Opin Immunol. 2020;62:22-30.
44.
Chowdhury M, Li CF, He Z, Lu Y, Liu XS, Wang YF, et al. Toll family members bind multiple Spatzle proteins and activate antimicrobial peptide gene expression in Drosophila. J Biol Chem. 2019;294(26):10172-81.
45.
Yang D, Biragyn A, Kwak LW, Oppenheim JJ. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 2002;23(6):291-6.
46.
Ageitos JM, Sánchez-Pérez A, Calo-Mata P, Villa TG. Antimicrobial peptides (AMPs): ancient compounds that represent novel weapons in the fight against bacteria. Biochem Pharmacol. 2017;133:117-38.
47.
Avila EE. Functions of antimicrobial peptides in vertebrates. Curr Protein Pept Sci. 2017;18(11):1098-119.
48.
Muncaster S, Kraakman K, Gibbons O, Mensink K, Forlenza M, Jacobson G, et al. Antimicrobial peptides within the Yellowtail Kingfish (Seriola lalandi). Dev Comp Immunol. 2018;80:67-80.
49.
van Harten RM, van Woudenbergh E, van Dijk A, Haagsman HP. Cathelicidins: immunomodulatory antimicrobials. Vaccines (Basel). 2018;6(3):63.
50.
Chen C, Wang A, Zhang F, Zhang M, Yang H, Li J, et al. The protective effect of fish-derived cathelicidins on bacterial infections in zebrafish, Danio rerio. Fish Shellfish Immunol. 2019;92:519-27.
51.
Patocka J, Nepovimova E, Klimova B, Wu Q, Kuca K. Antimicrobial peptides: amphibian host defense peptides. Curr Med Chem. 2019;26(32):5924-46.
52.
Wei L, Yang J, He X, Mo G, Hong J, Yan X, et al. Structure and function of a potent lipopolysaccharide-binding antimicrobial and anti-inflammatory peptide. J Med Chem. 2013;56(9):3546-56.
53.
Perez-Peinado C, Dias SA, Domingues MM, Benfield AH, Freire JM, Radis-Baptista G, et al. Mechanisms of bacterial membrane permeabilization by crotalicidin (Ctn) and its fragment Ctn(15–34), antimicrobial peptides from rattlesnake venom. J Biol Chem. 2018;293(5):1536-49.
54.
Rajasekaran G, Kumar SD, Yang S, Shin SY. The design of a cell-selective fowlicidin-1-derived peptide with both antimicrobial and anti-inflammatory activities. Eur J Med Chem. 2019;182:111623.
55.
Young-Speirs M, Drouin D, Cavalcante PA, Barkema HW, Cobo ER. Host defense cathelicidins in cattle: types, production, bioactive functions and potential therapeutic and diagnostic applications. Int J Antimicrob Agents. 2018;51(6):813-21.
56.
Harman RM, Yang S, He MK, Van de Walle GR. Antimicrobial peptides secreted by equine mesenchymal stromal cells inhibit the growth of bacteria commonly found in skin wounds. Stem Cell Res Ther. 2017;8(1):157.
57.
Huynh E, Penney J, Caswell J, Li J. Protective effects of protegrin in dextran sodium sulfate-induced murine colitis. Front Pharmacol. 2019;10:156.
58.
Reczyńska D, Zalewska M, Czopowicz M, Kaba J, Zwierzchowski L, Bagnicka E. Small ruminant lentivirus infection influences expression of acute phase proteins and cathelicidin genes in milk somatic cells and peripheral blood leukocytes of dairy goats. Vet Res. 2018;49(1):113.
59.
Panteleev PV, Bolosov IA, Kalashnikov AA, Kokryakov VN, Shamova OV, Emelianova AA, et al. Combined antibacterial effects of goat cathelicidins with different mechanisms of action. Front Microbiol. 2018;9:2983.
60.
Tedde V, Bronzo V, Puggioni GMG, Pollera C, Casula A, Curone G, et al. Milk cathelicidin and somatic cell counts in dairy goats along the course of lactation. J Dairy Res. 2019;86(2):217-21.
61.
de Lima M, da Silva RA, da Silva MF, da Silva PAB, Costa R, Teixeira JAC, et al. Brazilian kefir-fermented Sheep’s milk, a source of antimicrobial and antioxidant peptides. Probiotics Antimicrob Proteins. 2018;10(3):446-55.
62.
Coorens M, Schneider VAF, de Groot AM, van Dijk A, Meijerink M, Wells JM, et al. Cathelicidins inhibit Escherichia coli-induced TLR2 and TLR4 activation in a viability-dependent manner. J Immunol. 2017;199(4):1418-28.
63.
Schneider VA, Coorens M, Ordonez SR, Tjeerdsma-van Bokhoven JL, Posthuma G, van Dijk A, et al. Imaging the antimicrobial mechanism(s) of cathelicidin-2. Sci Rep. 2016;6:32948.
64.
Nakazawa M, Maeda S, Omori M, Kaji K, Yokoyama N, Nakagawa T, et al. Duodenal expression of antimicrobial peptides in dogs with idiopathic inflammatory bowel disease and intestinal lymphoma. Vet J. 2019;249:47-52.
65.
Peng H, Purkerson JM, Schwaderer AL, Schwartz GJ. Metabolic acidosis stimulates the production of the antimicrobial peptide cathelicidin in rabbit urine. Am J Physiol Renal Physiol. 2017;313(5):F1061-7.
66.
Nagaoka I, Tamura H, Reich J. Therapeutic potential of cathelicidin peptide LL-37, an antimicrobial agent, in a murine sepsis model. Int J Mol Sci. 2020;21(17):5973.
67.
Fruitwala S, El-Naccache DW, Chang TL. Multifaceted immune functions of human defensins and underlying mechanisms. Semin Cell Dev Biol. 2019;88:163-72.
68.
Pace BT, Lackner AA, Porter E, Pahar B. The role of defensins in HIV pathogenesis. Mediators Inflamm. 2017;2017:5186904.
69.
Contreras G, Shirdel I, Braun MS, Wink M. Defensins: transcriptional regulation and function beyond antimicrobial activity. Dev Comp Immunol. 2020;104:103556.
70.
Pasupuleti M, Schmidtchen A, Malmsten M. Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol. 2012;32(2):143-71.
71.
Gurao A, Kashyap SK, Singh R. Beta-defensins: an innate defense for bovine mastitis. Vet World. 2017;10(8):990-8.
72.
Tang KY, Wang X, Wan QH, Fang SG. A crucial role of paralogous betadefensin genes in the Chinese alligator innate immune system revealed by the first determination of a Crocodilia defensin cluster. Dev Comp Immunol. 2018;81:193-203.
73.
Wang R, Ma D, Lin L, Zhou C, Han Z, Shao Y, et al. Identification and characterization of an avian beta-defensin orthologue, avian betadefensin 9, from quails. Appl Microbiol Biotechnol. 2010;87(4):1395-405.
74.
Pei J, Jiang L. Antimicrobial peptide from mucus of Andrias davidianus: screening and purification by magnetic cell membrane separation technique. Int J Antimicrob Agents. 2017;50(1):41-6.
75.
Li T, Liu Q, Wang D, Li J. Characterization and antimicrobial mechanism of CF-14, a new antimicrobial peptide from the epidermal mucus of catfish. Fish Shellfish Immunol. 2019;92:881-8.
76.
Chang YL, Wang Z, Igawa S, Choi JE, Werbel T, Di Nardo A. Lipocalin 2: a new antimicrobial in mast cells. Int J Mol Sci. 2019;20(10):2380.
77.
Schneider JJ, Unholzer A, Schaller M, Schafer-Korting M, Korting HC. Human defensins. J Mol Med (Berl). 2005;83(8):587-95.
78.
Sørense O, Arnljots K, Cowland JB, Bainton DF, Borregaard N. The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils. Blood. 1997;90(7):2796-803.
79.
Pinheiro da Silva F, Machado MC. The dual role of cathelicidins in systemic inflammation. Immunol Lett. 2017;182:57-60.
80.
Varga JFA, Bui-Marinos MP, Katzenback BA. Frog skin innate immune defences: sensing and surviving pathogens. Front Immunol. 2018;9:3128.
81.
Pei J, Feng Z, Ren T, Sun H, Han H, Jin W, et al. Purification, characterization and application of a novel antimicrobial peptide from Andrias davidianus blood. Lett Appl Microbiol. 2018;66(1):38-43.
82.
Hui CY, Guo Y, Zhang W, Yang XQ, Gao CX, Yang XY. Isolation and characterization of antimicrobial peptides from healthy male urine. Pak J Pharm Sci. 2017;30(2):363-7.
83.
Wu CX, Liu ZF. Proteomic profiling of sweat exosome suggests its involvement in skin immunity. J Invest Dermatol. 2018;138(1):89-97.
84.
Correia A, Weimann A. Protein antibiotics: mind your language. Nat Rev Microbiol. 2021;19(1):7.
85.
Di Somma A, Moretta A, Canè C, Cirillo A, Duilio A. Antimicrobial and antibiofilm peptides. Biomolecules. 2020;10(4):652.
86.
Pirtskhalava M, Amstrong AA, Grigolava M, Chubinidze M, Alimbarashvili E, Vishnepolsky B, et al. DBAASP v3: database of antimicrobial/cytotoxic activity and structure of peptides as a resource for development of new therapeutics. Nucleic Acids Res. 2021;49(D1):D288-97.
87.
Dennison SR, Harris F, Mura M, Phoenix DA. An atlas of anionic antimicrobial peptides from amphibians. Curr Protein Pept Sci. 2018;19(8):823-38.
88.
Almarwani B, Phambu N, Hamada YZ, Sunda-Meya A. Interactions of an anionic antimicrobial peptide with Zinc(II): application to bacterial mimetic membranes. Langmuir. 2020;36(48):14554-62.
89.
de Haën C, Neurath H, Teller DC. The phylogeny of trypsin-related serine proteases and their zymogens. New methods for the investigation of distant evolutionary relationships. J Mol Biol. 1975;92(2):225-59.
90.
Miller A, Matera-Witkiewicz A, Mikolajczyk A, Watly J, Wilcox D, Witkowska D, et al. Zn-enhanced Asp-rich antimicrobial peptides: N-terminal coordination by Zn(II) and Cu(II), which distinguishes Cu(II) binding to different peptides. Int J Mol Sci. 2021;22(13):6971.
91.
Teixeira V, Feio MJ, Bastos M. Role of lipids in the interaction of antimicrobial peptides with membranes. Prog Lipid Res. 2012;51(2):149-77.
92.
Gennaro R, Zanetti M. Structural features and biological activities of the cathelicidin-derived antimicrobial peptides. Biopolymers. 2000;55(1):31-49.
93.
Lewies A, Wentzel JF, Jacobs G, Du Plessis LH. The potential use of natural and structural analogues of antimicrobial peptides in the fight against neglected tropical diseases. Molecules. 2015;20(8):15392-433.
94.
Aidoukovitch A, Dahl S, Falt F, Nebel D, Svensson D, Tufvesson E, et al. Antimicrobial peptide LL-37 and its pro-form, hCAP18, in desquamated epithelial cells of human whole saliva. Eur J Oral Sci. 2020;128(1):1-6.
95.
Fabisiak A, Murawska N, Fichna J. LL-37: cathelicidin-related antimicrobial peptide with pleiotropic activity. Pharmacol Rep. 2016;68(4):802-8.
96.
Johansson J, Gudmundsson GH, Rottenberg ME, Berndt KD, Agerberth B. Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J Biol Chem. 1998;273(6):3718-24.
97.
Koehbach J, Craik DJ. The vast structural diversity of antimicrobial peptides. Trends Pharmacol Sci. 2019;40(7):517-28.
98.
Zhao H. Mode of action of antimicrobial peptides [academic dissertation]. Helsinki: University of Helsinki. 2003;47(3):965-71.
99.
Klüver E, Schulz-Maronde S, Scheid S, Meyer B, Forssmann WG, Adermann K. Structure-activity relation of human beta-defensin 3: influence of disulfide bonds and cysteine substitution on antimicrobial activity and cytotoxicity. Biochemistry. 2005;44(28):9804-16.
100.
Mattar EH, Almehdar HA, Yacoub HA, Uversky VN, Redwan EM. Antimicrobial potentials and structural disorder of human and animal defensins. Cytokine Growth Factor Rev. 2016;28:95-111.
101.
Lehrer RI, Lu W. Alpha-defensins in human innate immunity. Immunol Rev. 2012;245(1):84-112.
102.
Tai KP, Le VV, Selsted ME, Ouellette AJ. Hydrophobic determinants of α-defensin bactericidal activity. Infect Immun. 2014;82(6):2195-202.
103.
Koehbach J. Structure-activity relationships of insect defensins. Front Chem. 2017;5:45.
104.
Guyot N, Meudal H, Trapp S, Iochmann S, Silvestre A, Jousset G, et al. Structure, function, and evolution of Gga-AvBD11, the archetype of the structural avian-double-beta-defensin family. Proc Natl Acad Sci U S A. 2020;117(1):337-45.
105.
Sitaram N. Antimicrobial peptides with unusual amino acid compositions and unusual structures. Curr Med Chem. 2006;13(6):679-96.
106.
Selsted ME. Theta-defensins: cyclic antimicrobial peptides produced by binary ligation of truncated alpha-defensins. Curr Protein Pept Sci. 2004;5(5):365-71.
107.
Conibear AC, Rosengren KJ, Daly NL, Henriques ST, Craik DJ. The cyclic cystine ladder in theta-defensins is important for structure and stability, but not antibacterial activity. J Biol Chem. 2013;288(15):10830-40.
108.
Holani R, Shah C, Haji Q, Inglis GD, Uwiera RRE, Cobo ER. Prolinearginine rich (PR-39) cathelicidin: structure, expression and functional implication in intestinal health. Comp Immunol Microbiol Infect Dis. 2016;49:95-101.
109.
Hernandez-Flores JL, Rodriguez MC, Gastelum Arellanez A, Alvarez-Morales A, Avila EE. Effect of recombinant prophenin 2 on the integrity and viability of Trichomonas vaginalis. Biomed Res Int. 2015;2015:430436.
110.
Smirnova MP, Kolodkin NI, Kolobov AA, Afonin VG, Afonina IV, Stefanenko LI, et al. Indolicidin analogs with broad-spectrum antimicrobial activity and low hemolytic activity. Peptides. 2020;132:170356.
111.
Khurshid Z, Najeeb S, Mali M, Moin SF, Raza SQ, Zohaib S, et al. Histatin peptides: pharmacological functions and their applications in dentistry. Saudi Pharm J. 2017;25(1):25-31.
112.
Starling S. Innate immunity: a new way out for lysozyme. Nat Rev Gastroenterol Hepatol. 2017;14(10):567.
113.
Ragland SA, Criss AK. From bacterial killing to immune modulation: recent insights into the functions of lysozyme. PLoS Pathog. 2017;13(9):e1006512.
114.
Zhang C, Zhang J, Liu M, Huang M. Molecular cloning, expression and antibacterial activity of goose-type lysozyme gene in Microptenus salmoides. Fish Shellfish Immunol. 2018;82:9-16.
115.
Ibrahim HR, Thomas U, Pellegrini A. A helix-loop-helix peptide at the upper lip of the active site cleft of lysozyme confers potent antimicrobial activity with membrane permeabilization action. J Biol Chem. 2001;276(47):43767-74.
116.
Toda H, Williams JA, Gulledge M, Sehgal A. A sleep-inducing gene, nemuri, links sleep and immune function in Drosophila. Science. 2019;363(6426):509-15.
117.
Harford C, Sarkar B. Amino terminal Cu(II)- and Ni(II)-binding (ATCUN) motif of proteins and peptides: metal binding, DNA cleavage, and other properties. Acc Chem Res. 1997;30:123-30.
118.
Portelinha J, Duay SS, Yu SI, Heilemann K, Libardo MDJ, Juliano SA, et al. Antimicrobial peptides and copper(II) ions: novel therapeutic opportunities. Chem Rev. 2021;121(4):2648-712.
119.
Wende C, Kulak N. Fluorophore ATCUN complexes: combining agent and probe for oxidative DNA cleavage. Chem Commun (Camb). 2015;51(62):12395-8.
120.
Heinrich J, König NF, Sobottka S, Sarkar B, Kulak N. Flexible vs. rigid bis(2-benzimidazolyl) ligands in Cu(II) complexes: impact on redox chemistry and oxidative DNA cleavage activity. J Inorg Biochem. 2019;194:223-32.
121.
Lin TY, Weibel DB. Organization and function of anionic phospholipids in bacteria. Appl Microbiol Biotechnol. 2016;100(10):4255-67.
122.
Enoki TA, Moreira-Silva I, Lorenzon EN, Cilli EM, Perez KR, Riske KA, et al. Antimicrobial peptide K0-W6-Hya1 induces stable structurally modified lipid domains in anionic membranes. Langmuir. 2018;34(5):2014-25.
123.
Vance JE. Phospholipid synthesis and transport in mammalian cells. Traffic. 2015;16(1):1-18.
124.
Florek OB, Clifton LA, Wilde M, Arnold T, Green RJ, Frazier RA. Lipid composition in fungal membrane models: effect of lipid fluidity. Acta Crystallogr D Struct Biol. 2018;74(Pt 12):1233-44.
125.
Renne MF, de Kroon A. The role of phospholipid molecular species in determining the physical properties of yeast membranes. FEBS Lett. 2018;592(8):1330-45.
126.
Baxter AA, Lay FT, Poon IKH, Kvansakul M, Hulett MD. Tumor cell membrane-targeting cationic antimicrobial peptides: novel insights into mechanisms of action and therapeutic prospects. Cell Mol Life Sci. 2017;74(20):3809-25.
127.
Groux-Degroote S, Guérardel Y, Delannoy P. Gangliosides: structures, biosynthesis, analysis, and roles in cancer. ChemBioChem. 2017;18(13):1146-54.
128.
Vicente CM, da Silva DA, Sartorio PV, Silva TD, Saad SS, Nader HB, et al. Heparan sulfate proteoglycans in human colorectal cancer. Anal Cell Pathol (Amst). 2018;2018:8389595.
129.
Riedl S, Zweytick D, Lohner K. Membrane-active host defense peptides–challenges and perspectives for the development of novel anticancer drugs. Chem Phys Lipids. 2011;164(8):766-81.
130.
Rajagopal M, Walker S. Envelope structures of gram-positive bacteria. Curr Top Microbiol Immunol. 2017;404:1-44.
131.
Baek MH, Kamiya M, Kushibiki T, Nakazumi T, Tomisawa S, Abe C, et al. Lipopolysaccharide-bound structure of the antimicrobial peptide cecropin P1 determined by nuclear magnetic resonance spectroscopy. J Pept Sci. 2016;22(4):214-21.
132.
Malanovic N, Lohner K. Gram-positive bacterial cell envelopes: the impact on the activity of antimicrobial peptides. Biochim Biophys Acta. 2016;1858(5):936-46.
133.
Bechinger B, Gorr SU. Antimicrobial peptides: mechanisms of action and resistance. J Dent Res. 2017;96(3):254-60.
134.
Hong J, Lu X, Deng Z, Xiao S, Yuan B, Yang K. How melittin inserts into cell membrane: conformational changes, inter-peptide cooperation, and disturbance on the membrane. Molecules. 2019;24(9):1775.
135.
Oliva R, Del Vecchio P, Grimaldi A, Notomista E, Cafaro V, Pane K, et al. Membrane disintegration by the antimicrobial peptide (P)GKY20: lipid segregation and domain formation. Phys Chem Chem Phys. 2019;21(7):3989-98.
136.
Queme-Pena M, Juhasz T, Mihaly J, Cs Szigyarto I, Horvati K, Bosze S, et al. Manipulating active structure and function of cationic antimicrobial peptide CM15 with the polysulfonated drug suramin: a step closer to in vivo complexity. ChemBioChem. 2019;20(12):1578-90.
137.
Lee TH, Hall KN, Aguilar MI. Antimicrobial peptide structure and mechanism of action: a focus on the role of membrane structure. Curr Top Med Chem. 2016;16(1):25-39.
138.
Abrunhosa F, Faria S, Gomes P, Tomaz I, Pessoa JC, Andreu D, et al. Interaction and lipid-induced conformation of two cecropin-melittin hybrid peptides depend on peptide and membrane composition. J Phys Chem B. 2005;109(36):17311-9.
139.
Strandberg E, Wadhwani P, Tremouilhac P, Durr UH, Ulrich AS. Solid-state NMR analysis of the PGLa peptide orientation in DMPC bilayers: structural fidelity of 2H-labels versus high sensitivity of 19F-NMR. Biophys J. 2006;90(5):1676-86.
140.
Silva JP, Appelberg R, Gama FM. Antimicrobial peptides as novel antituberculosis therapeutics. Biotechnol Adv. 2016;34(5):924-40.
141.
Kumar P, Kizhakkedathu JN, Straus SK. Antimicrobial peptides: diversity, mechanism of action and strategies to improve the activity and biocompatibility in vivo. Biomolecules. 2018;8(1):4.
142.
Hale JD, Hancock RE. Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev Anti Infect Ther. 2007;5(6):951-9.
143.
Hancock RE, Patrzykat A. Clinical development of cationic antimicrobial peptides: from natural to novel antibiotics. Curr Drug Targets Infect Disord. 2002;2(1):79-83.
144.
Dennison SR, Morton LH, Harris F, Phoenix DA. Low pH enhances the action of maximin H5 against Staphylococcus aureus and helps mediate lysylated phosphatidylglycerol-induced resistance. Biochemistry. 2016;55(27):3735-51.
145.
Li S, Hao L, Bao W, Zhang P, Su D, Cheng Y, et al. A novel short anionic antibacterial peptide isolated from the skin of Xenopus laevis with broad antibacterial activity and inhibitory activity against breast cancer cell. Arch Microbiol. 2016;198(5):473-82.
146.
Sowa-Jasilek A, Zdybicka-Barabas A, Staczek S, Pawlikowska-Pawlega B, Grygorczuk-Planeta K, Skrzypiec K, et al. Antifungal activity of anionic defense peptides: insight into the action of galleria mellonella anionic peptide 2. Int J Mol Sci. 2020;21(6):1912.
147.
Mandal SM, Khan J, Mahata D, Saha S, Sengupta J, Silva ON, et al. A self-assembled clavanin A-coated amniotic membrane scaffold for the prevention of biofilm formation by ocular surface fungal pathogens. Biofouling. 2017;33(10):881-91.
148.
Fiorentino F, Sauer JB, Qiu X, Corey RA, Cassidy CK, Mynors-Wallis B, et al. Dynamics of an LPS translocon induced by substrate and an antimicrobial peptide. Nat Chem Biol. 2021;17(2):187-95.
149.
Cardoso MH, Meneguetti BT, Costa BO, Buccini DF, Oshiro KGN, Preza SLE, et al. Non-lytic antibacterial peptides that translocate through bacterial membranes to act on intracellular targets. Int J Mol Sci. 2019;20(19):4877.
150.
Uyterhoeven ET, Butler CH, Ko D, Elmore DE. Investigating the nucleic acid interactions and antimicrobial mechanism of buforin II. FEBS Lett. 2008;582(12):1715-8.
151.
Zhang Y, Liu S, Li S, Cheng Y, Nie L, Wang G, et al. Novel short antimicrobial peptide isolated from Xenopus laevis skin. J Pept Sci. 2017;23(5):403-9.
152.
Chen X, Li L. Non-membrane mechanisms of antimicrobial peptide P7 against Escherichia coli. Wei Sheng Wu Xue Bao. 2016;56(11):1737-45.
153.
Kang HK, Seo CH, Luchian T, Park Y. Pse-T2, an antimicrobial peptide with high-level, broad-spectrum antimicrobial potency and skin biocompatibility against multidrug-resistant Pseudomonas aeruginosa infection. Antimicrob Agents Chemother. 2018;62(12):e01493-e1518.
154.
Wu C, Biswas S, Garcia De Gonzalo CV, van der Donk WA. Investigations into the mechanism of action of sublancin. ACS Infect Dis. 2019;5(3):454-9.
155.
Boman HG, Agerberth B, Boman A. Mechanisms of action on Escherichia coli of cecropin P1 and PR-39, two antibacterial peptides from pig intestine. Infect Immun. 1993;61(7):2978-84.
156.
Graf M, Mardirossian M, Nguyen F, Seefeldt AC, Guichard G, Scocchi M, et al. Proline-rich antimicrobial peptides targeting protein synthesis. Nat Prod Rep. 2017;34(7):702-11.
157.
Roy RN, Lomakin IB, Gagnon MG, Steitz TA. The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin. Nat Struct Mol Biol. 2015;22(6):466-9.
158.
Florin T, Maracci C, Graf M, Karki P, Klepacki D, Berninghausen O, et al. An antimicrobial peptide that inhibits translation by trapping release factors on the ribosome. Nat Struct Mol Biol. 2017;24(9):752-7.
159.
Mardirossian M, Barriere Q, Timchenko T, Muller C, Pacor S, Mergaert P, et al. Fragments of the nonlytic proline-rich antimicrobial peptide Bac5 Kill Escherichia coli cells by inhibiting protein synthesis. Antimicrob Agents Chemother. 2018;62(8):e00534-e618.
160.
Otvos L Jr, Rogers ME, Consolvo PJ, Condie BA, Lovas S, et al. Interaction between heat shock proteins and antimicrobial peptides. Biochemistry. 2000;39(46):14150-9.
161.
Kragol G, Lovas S, Varadi G, Condie BA, Hoffmann R, Otvos L Jr. The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry. 2001;40(10):3016-26.
162.
Braffman NR, Piscotta FJ, Hauver J, Campbell EA, Link AJ, Darst SA. Structural mechanism of transcription inhibition by lasso peptides microcin J25 and capistruin. Proc Natl Acad Sci U S A. 2019;116(4):1273-8.
163.
Yang H, Fu J, Zhao Y, Shi H, Hu H, Wang H. Escherichia coli PagP enzyme-based de novo design and in vitro activity of antibacterial peptide LL-37. Med Sci Monit. 2017;23:2558-64.
164.
Hou X, Feng C, Li S, Luo Q, Shen G, Wu H, et al. Mechanism of antimicrobial peptide NP-6 from Sichuan pepper seeds against E. coli and effects of different environmental factors on its activity. Appl Microbiol Biotechnol. 2019;103(16):6593-604.
165.
Lehrer RI, Barton A, Daher KA, Harwig SS, Ganz T, Selsted ME. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J Clin Invest. 1989;84(2):553-61.
166.
de Leeuw E, Li C, Zeng P, Li C, Diepeveen-de Buin M, Lu WY, et al. Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS Lett. 2010;584(8):1543-8.
167.
Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455-9.
168.
Manabe T, Kawasaki K. D-form KLKLLLLLKLK-NH2 peptide exerts higher antimicrobial properties than its L-form counterpart via an association with bacterial cell wall components. Sci Rep. 2017;7:43384.
169.
Wilmes M, Stockem M, Bierbaum G, Schlag M, Gotz F, Tran DQ, et al. Killing of Staphylococci by theta-defensins involves membrane impairment and activation of autolytic enzymes. Antibiotics (Basel). 2014;3(4):617-31.
170.
Yasir M, Dutta D, Willcox MDP. Mode of action of the antimicrobial peptide Mel4 is independent of Staphylococcus aureus cell membrane permeability. PLoS ONE. 2019;14(7):e0215703.
171.
Lv Y, Shao G, Zhang Q, Wang X, Meng Y, Wang L, et al. The antimicrobial peptide PFR induces necroptosis mediated by ER stress and elevated cytoplasmic calcium and mitochondrial ROS levels: cooperation with Ara-C to act against acute myeloid leukemia. Signal Transduct Target Ther. 2019;4:38.
172.
Kurpe SR, Grishin SY, Surin AK, Panfilov AV, Slizen MV, Chowdhury SD, et al. Antimicrobial and amyloidogenic activity of peptides. Can antimicrobial peptides be used against SARS-CoV-2? Int J Mol Sci. 2020;21(24):9552.
173.
Zhang M, Zhao J, Zheng J. Molecular understanding of a potential functional link between antimicrobial and amyloid peptides. Soft Matter. 2014;10(38):7425-51.
174.
Kurpe SR, Grishin SY, Surin AK, Selivanova OM, Fadeev RS, Dzhus UF, et al. Antimicrobial and amyloidogenic activity of peptides synthesized on the basis of the ribosomal S1 protein from Thermus thermophilus. Int J Mol Sci. 2020;21(17):6382.
175.
Mokoena MP. Lactic acid bacteria and their bacteriocins: classification, biosynthesis and applications against uropathogens: a mini-review. Molecules. 2017;22(8):1255.
176.
Wang S, Fang Q, Lu Z, Gao Y, Trembleau L, Ebel R, et al. Discovery and biosynthetic investigation of a new antibacterial dehydrated nonribosomal tripeptide. Angew Chem Int Ed Engl. 2021;60(6):3229-37.
177.
Galvan Marquez IJ, McKay B, Wong A, Cheetham JJ, Bean C, Golshani A, et al. Mode of action of nisin on Escherichia coli. Can J Microbiol. 2020;66(2):161-8.
178.
Tong Z, Zhang Y, Ling J, Ma J, Huang L, Zhang L. An in vitro study on the effects of nisin on the antibacterial activities of 18 antibiotics against Enterococcus faecalis. PLoS ONE. 2014;9(2):e89209.
179.
Li C, Hong PP, Yang MC, Zhao XF, Wang JX. FOXO regulates the expression of antimicrobial peptides and promotes phagocytosis of hemocytes in shrimp antibacterial immunity. PLoS Pathog. 2021;17(4):e1009479.
180.
Rodríguez-Rojas A, Baeder DY, Johnston P, Regoes RR, Rolff J. Bacteria primed by antimicrobial peptides develop tolerance and persist. PLoS Pathog. 2021;17(3):e1009443.
181.
Liang X, Zhang X, Lian K, Tian X, Zhang M, Wang S, et al. Antiviral effects of Bovine antimicrobial peptide against TGEV in vivo and in vitro. J Vet Sci. 2020;21(5):e80.
182.
Yasin B, Wang W, Pang M, Cheshenko N, Hong T, Waring AJ, et al. Theta defensins protect cells from infection by herpes simplex virus by inhibiting viral adhesion and entry. J Virol. 2004;78(10):5147-56.
183.
Yasin B, Pang M, Turner JS, Cho Y, Dinh NN, Waring AJ, et al. Evaluation of the inactivation of infectious Herpes simplex virus by host-defense peptides. Eur J Clin Microbiol Infect Dis. 2000;19(3):187-94.
184.
Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, et al. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One. 2011;6(10):e25333.
185.
Bergman P, Walter-Jallow L, Broliden K, Agerberth B, Soderlund J. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Curr HIV Res. 2007;5(4):410-5.
186.
Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol. 2013;94(Pt 1):40-9.
187.
Howell MD, Jones JF, Kisich KO, Streib JE, Gallo RL, Leung DY. Selective killing of vaccinia virus by LL-37: implications for eczema vaccinatum. J Immunol. 2004;172(3):1763-7.
188.
Howell MD, Wollenberg A, Gallo RL, Flaig M, Streib JE, Wong C, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836-41.
189.
Ahmed A, Siman-Tov G, Hall G, Bhalla N, Narayanan A. Human antimicrobial peptides as therapeutics for viral infections. Viruses. 2019;11(8):704.
190.
Yu J, Dai Y, Fu Y, Wang K, Yang Y, Li M, et al. Cathelicidin antimicrobial peptides suppress EV71 infection via regulating antiviral response and inhibiting viral binding. Antiviral Res. 2021;187:105021.
191.
LeMessurier KS, Lin Y, McCullers JA, Samarasinghe AE. Antimicrobial peptides alter early immune response to influenza A virus infection in C57BL/6 mice. Antiviral Res. 2016;133:208-17.
192.
Vilas Boas LC, de Lima LM, Migliolo L, Mendes GD, de Jesus MG, Franco OL, et al. Linear antimicrobial peptides with activity against herpes simplex virus 1 and Aichi virus. Biopolymers. 2017. https://doi.org/10.1002/bip.22871.
193.
Marcocci ME, Amatore D, Villa S, Casciaro B, Aimola P, Franci G, et al. The amphibian antimicrobial peptide temporin B inhibits in vitro herpes simplex virus 1 infection. Antimicrob Agents Chemother. 2018;62(5):e02367-417.
194.
De Angelis M, Casciaro B, Genovese A, Brancaccio D, Marcocci ME, Novellino E, et al. Temporin G, an amphibian antimicrobial peptide against influenza and parainfluenza respiratory viruses: insights into biological activity and mechanism of action. FASEB J. 2021;35(2):e21358.
195.
Boffert R, Businger R, Preiss H, Ehmann D, Truffault V, Simon C, et al. The human alpha-defensin-derived peptide HD5(1–9) inhibits cellular attachment and entry of human cytomegalovirus. Antiviral Res. 2020;177:104779.
196.
He M, Zhang H, Li Y, Wang G, Tang B, Zhao J, et al. Cathelicidinderived antimicrobial peptides inhibit Zika virus through direct inactivation and interferon pathway. Front Immunol. 2018;9:722.
197.
Monteiro JMC, Oliveira MD, Dias RS, Nacif-Marcal L, Feio RN, Ferreira SO, et al. The antimicrobial peptide HS-1 inhibits dengue virus infection. Virology. 2018;514:79-87.
198.
Hu H, Guo N, Chen S, Guo X, Liu X, Ye S, et al. Antiviral activity of Piscidin 1 against pseudorabies virus both in vitro and in vivo. Virol J. 2019;16(1):95.
199.
Uchio E, Inoue H, Kadonosono K. Anti-adenoviral effects of human cationic antimicrobial protein-18/LL-37, an antimicrobial peptide, by quantitative polymerase chain reaction. Korean J Ophthalmol. 2013;27(3):199-203.
200.
Sousa FH, Casanova V, Findlay F, Stevens C, Svoboda P, Pohl J, et al. Cathelicidins display conserved direct antiviral activity towards rhinovirus. Peptides. 2017;95:76-83.
201.
Chessa C, Bodet C, Jousselin C, Wehbe M, Leveque N, Garcia M. Antiviral and immunomodulatory properties of antimicrobial peptides produced by human keratinocytes. Front Microbiol. 2020;11:1155.
202.
Holly MK, Diaz K, Smith JG. Defensins in viral infection and pathogenesis. Annu Rev Virol. 2017;4(1):369-91.
203.
Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12(4):988.
204.
Ash MM, Phillips CM. Parasitic diseases with cutaneous manifestations. N C Med J. 2016;77(5):350-4.
205.
Theel ES, Pritt BS. Parasites. Microbiol Spectr. 2016. https://doi.org/10.1128/microbiolspec.DMIH2-0013-2015.
206.
Parise ME, Hotez PJ, Slutsker L. Neglected parasitic infections in the United States: needs and opportunities. Am J Trop Med Hyg. 2014;90(5):783-5.
207.
Uraki S, Sugimoto K, Shiraki K, Tameda M, Inagaki Y, Ogura S, et al. Human beta-defensin-3 inhibits migration of colon cancer cells via downregulation of metastasis-associated 1 family, member 2 expression. Int J Oncol. 2014;45(3):1059-64.
208.
Pitale DM, Kaur G, Baghel M, Kaur KJ, Shaha C. Halictine-2 antimicrobial peptide shows promising anti-parasitic activity against Leishmania spp. Exp Parasitol. 2020;218:107987.
209.
Tinoco-Nunes B, Telleria EL, da Silva-Neves M, Marques C, Azevedo-Brito DA, Pitaluga AN, et al. The sandfly Lutzomyia longipalpis LL5 embryonic cell line has active Toll and Imd pathways and shows immune responses to bacteria, yeast and Leishmania. Parasit Vectors. 2016;9:222.
210.
Fang Y, He X, Zhang P, Shen C, Mwangi J, Xu C, et al. In vitro and in vivo antimalarial activity of LZ1, a peptide derived from snake cathelicidin. Toxins (Basel). 2019;11(7):379.
211.
Kuckelhaus SA, Leite JR, Muniz-Junqueira MI, Sampaio RN, Bloch C Jr, Tosta CE. Antiplasmodial and antileishmanial activities of phylloseptin-1, an antimicrobial peptide from the skin secretion of Phyllomedusa azurea (Amphibia). Exp Parasitol. 2009;123(1):11-6.
212.
Hancock RE, Haney EF, Gill EE. The immunology of host defence peptides: beyond antimicrobial activity. Nat Rev Immunol. 2016;16(5):321-34.
213.
Mack MR, Kim BS. Superficial immunity: antimicrobial responses are more than skin deep. Immunity. 2016;45(1):6-8.
214.
Kang HK, Lee HH, Seo CH, Park Y. Antimicrobial and immunomodulatory properties and applications of marine-derived proteins and peptides. Mar Drugs. 2019;17(6):350.
215.
Jirillo E, Magrone T. Editorial: antimicrobial peptides as mediators of innate immunity. Curr Pharm Des. 2018;24(10):1041-2.
216.
Neumann A, Vollger L, Berends ET, Molhoek EM, Stapels DA, Midon M, et al. Novel role of the antimicrobial peptide LL-37 in the protection of neutrophil extracellular traps against degradation by bacterial nucleases. J Innate Immun. 2014;6(6):860-8.
217.
Tjabringa GS, Ninaber DK, Drijfhout JW, Rabe KF, Hiemstra PS. Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors. Int Arch Allergy Immunol. 2006;140(2):103-12.
218.
Yang D, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med. 2000;192(7):1069-74.
219.
Agier J, Brzezińska-Błaszczyk E. Cathelicidins and defensins regulate mast cell antimicrobial activity. Postepy Hig Med Dosw (Online). 2016;70:618-36.
220.
Lishko VK, Moreno B, Podolnikova NP, Ugarova TP. Identification of human cathelicidin peptide LL-37 as a ligand for macrophage integrin αMβ2 (Mac-1, CD11b/CD18) that promotes phagocytosis by opsonizing bacteria. Res Rep Biochem. 2016;2016(6):39-55.
221.
Cao Y, Chen F, Sun Y, Hong H, Wen Y, Lai Y, et al. LL-37 promotes neutrophil extracellular trap formation in chronic rhinosinusitis with nasal polyps. Clin Exp Allergy. 2019;49(7):990-9.
222.
Yoon SH, Hwang I, Lee E, Cho HJ, Ryu JH, Kim TG, et al. Antimicrobial peptide Ll-37 drives rosacea-like skin inflammation in an Nlrp3-dependent manner. J Invest Dermatol. 2021;S0022-202X(21)01009-5.
223.
Schiffmann S, Gunne S, Henke M, Ulshofer T, Steinhilber D, Sethmann A, et al. Sodium bituminosulfonate used to treat rosacea modulates generation of inflammatory mediators by primary human neutrophils. J Inflamm Res. 2021;14:2569-82.
224.
Bąbolewska E, Brzezińska-Błaszczyk E. Human-derived cathelicidin LL-37 directly activates mast cells to proinflammatory mediator synthesis and migratory response. Cell Immunol. 2015;293(2):67-73.
225.
Agier J, Brzezińska-Błaszczyk E, Żelechowska P, Wiktorska M, Pietrzak J, Różalska S. Cathelicidin LL-37 affects surface and intracellular Toll-like receptor expression in tissue mast cells. J Immunol Res. 2018;2018:7357162.
226.
Bowdish DM, Davidson DJ, Speert DP, Hancock RE. The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes. J Immunol. 2004;172(6):3758-65.
227.
Nakamura K, Sakuragi N, Takakuwa A, Ayabe T. Paneth cell α-defensins and enteric microbiota in health and disease. Biosci Microbiota Food Health. 2016;35(2):57-67.
228.
Takakuwa A, Nakamura K, Kikuchi M, Sugimoto R, Ohira S, Yokoi Y, et al. Butyric acid and leucine induce alpha-defensin secretion from small intestinal paneth cells. Nutrients. 2019;11(11):2817.
229.
Xu D, Lu W. Defensins: a double-edged sword in host immunity. Front Immunol. 2020;11:764.
230.
Soehnlein O, Kai-Larsen Y, Frithiof R, Sorensen OE, Kenne E, Scharffetter-Kochanek K, et al. Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages. J Clin Invest. 2008;118(10):3491-502.
231.
Niyonsaba F, Ushio H, Nakano N, Ng W, Sayama K, Hashimoto K, et al. Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J Invest Dermatol. 2007;127(3):594-604.
232.
Medina Santos CE, Lopez Hurtado CN, Rivas Santiago B, Gonzalez-Amaro R, Catano Canizales YG, Martinez Fierro ML, et al. LL-37, HNP-1, and HBD2/3 modulate the secretion of cytokines TNF-alpha, IL-6, IFN-gamma, IL-10 and MMP1 in human primary cell cultures. Eur Cytokine Netw. 2016;27(3):68-74.
233.
Burgey C, Kern WV, Römer W, Sakinc T, Rieg S. The innate defense antimicrobial peptides hBD3 and RNase7 are induced in human umbilical vein endothelial cells by classical inflammatory cytokines but not Th17 cytokines. Microbes Infect. 2015;17(5):353-9.
234.
Huang C, Yang X, Huang J, Liu X, Yang X, Jin H, et al. Porcine betadefensin 2 provides protection against bacterial infection by a direct bactericidal activity and alleviates inflammation via interference with the TLR4/NF-kappaB pathway. Front Immunol. 2019;10:1673.
235.
Sechet E, Telford E, Bonamy C, Sansonetti PJ, Sperandio B. Natural molecules induce and synergize to boost expression of the human antimicrobial peptide β-defensin-3. Proc Natl Acad Sci U S A. 2018;115(42):E9869-78.
236.
Xu D, Liao C, Zhang B, Tolbert WD, He W, Dai Z, et al. Human enteric α-defensin 5 promotes Shigella infection by enhancing bacterial adhesion and invasion. Immunity. 2018;48(6):1233-44.
237.
Xu D, Liao C, Xiao J, Fang K, Zhang W, Yuan W, et al. Human enteric defensin 5 promotes Shigella infection of macrophages. Infect Immun. 2019;88(1):e00769-e819.
238.
Prasad SV, Fiedoruk K, Daniluk T, Piktel E, Bucki R. Expression and function of host defense peptides at inflammation sites. Int J Mol Sci. 2019;21(1):104.
239.
Hosoda H, Nakamura K, Hu Z, Tamura H, Reich J, Kuwahara-Arai K, et al. Antimicrobial cathelicidin peptide LL37 induces NET formation and suppresses the inflammatory response in a mouse septic model. Mol Med Rep. 2017;16(4):5618-26.
240.
Zhang Z, Le K, La Placa D, Armstrong B, Miller MM, Shively JE. CXCR2 specific endocytosis of immunomodulatory peptide LL-37 in human monocytes and formation of LL-37 positive large vesicles in differentiated monoosteophils. Bone Rep. 2020;12:100237.
241.
Alalwani SM, Sierigk J, Herr C, Pinkenburg O, Gallo R, Vogelmeier C, et al. The antimicrobial peptide LL-37 modulates the inflammatory and host defense response of human neutrophils. Eur J Immunol. 2010;40(4):1118-26.
242.
Luo XL, Li JX, Huang HR, Duan JL, Dai RX, Tao RJ, et al. LL37 Inhibits Aspergillus fumigatus infection via directly binding to the fungus and preventing excessive inflammation. Front Immunol. 2019;10:283.
243.
Zhang C, Yang M, Ericsson AC. Antimicrobial peptides: potential application in liver cancer. Front Microbiol. 2019;10:1257.
244.
Jin G, Weinberg A. Human antimicrobial peptides and cancer. Semin Cell Dev Biol. 2019;88:156-62.
245.
Niemirowicz K, Prokop I, Wilczewska AZ, Wnorowska U, Piktel E, Watek M, et al. Magnetic nanoparticles enhance the anticancer activity of cathelicidin LL-37 peptide against colon cancer cells. Int J Nanomedicine. 2015;10:3843-53.
246.
Kuroda K, Fukuda T, Isogai H, Okumura K, Krstic-Demonacos M, Isogai E. Antimicrobial peptide FF/CAP18 induces apoptotic cell death in HCT116 colon cancer cells via changes in the metabolic profile. Int J Oncol. 2015;46(4):1516-26.
247.
Piktel E, Niemirowicz K, Wnorowska U, Watek M, Wollny T, Gluszek K, et al. The role of cathelicidin LL-37 in cancer development. Arch Immunol Ther Exp (Warsz). 2016;64(1):33-46.
248.
Ren SX, Cheng AS, To KF, Tong JH, Li MS, Shen J, et al. Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res. 2012;72(24):6512-23.
249.
Wang J, Cheng M, Law IKM, Ortiz C, Sun M, Koon HW. Cathelicidin suppresses colon cancer metastasis via a P2RX7-dependent mechanism. Mol Ther Oncolytics. 2019;12:195-203.
250.
Hayashi M, Kuroda K, Ihara K, Iwaya T, Isogai E. Suppressive effect of an analog of the antimicrobial peptide of LL37 on colon cancer cells via exosome-encapsulated miRNAs. Int J Mol Med. 2018;42(6):3009-16.
251.
Wu WK, Sung JJ, To KF, Yu L, Li HT, Li ZJ, et al. The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells. J Cell Physiol. 2010;223(1):178-86.
252.
Maraming P, Klaynongsruang S, Boonsiri P, Peng SF, Daduang S, Leelayuwat C, et al. The cationic cell-penetrating KT2 peptide promotes cell membrane defects and apoptosis with autophagy inhibition in human HCT 116 colon cancer cells. J Cell Physiol. 2019;234(12):22116-29.
253.
Maijaroen S, Jangpromma N, Daduang J, Klaynongsruang S. KT2 and RT2 modified antimicrobial peptides derived from Crocodylus siamensis Leucrocin I show activity against human colon cancer HCT-116 cells. Environ Toxicol Pharmacol. 2018;62:164-76.
254.
Dia VP, Krishnan HB. BG-4, a novel anticancer peptide from bitter gourd (Momordica charantia), promotes apoptosis in human colon cancer cells. Sci Rep. 2016;6:33532.
255.
Chen YC, Tsai TL, Ye XH, Lin TH. Anti-proliferative effect on a colon adenocarcinoma cell line exerted by a membrane disrupting antimicrobial peptide KL15. Cancer Biol Ther. 2015;16(8):1172-83.
256.
Chen X, Zou X, Qi G, Tang Y, Guo Y, Si J, et al. Roles and mechanisms of human cathelicidin LL-37 in cancer. Cell Physiol Biochem. 2018;47(3):1060-73.
257.
Chen J, Shin VY, Ho JC, Siu MT, Cheuk IW, Kwong A. Functional implications of cathelicidin antimicrobial protein in breast cancer and tumor-associated macrophage microenvironment. Biomolecules. 2020;10(5):688.
258.
Habes C, Weber G, Goupille C. Sulfated glycoaminoglycans and proteoglycan syndecan-4 are involved in membrane fixation of LL-37 and its pro-migratory effect in breast cancer cells. Biomolecules. 2019;9(9):481.
259.
Lu Q, Quan W, Wu J, Zhang X, Ma W, Pang L, et al. Effect of antibacterial peptide hCAP18/LL-37 on ovarian cancer microenvironment and the regulatory mechanism of its expression. Zhonghua Zhong Liu Za Zhi. 2015;37(10):725-30.
260.
Jia J, Zheng Y, Wang W, Shao Y, Li Z, Wang Q, et al. Antimicrobial peptide LL-37 promotes YB-1 expression, and the viability, migration and invasion of malignant melanoma cells. Mol Med Rep. 2017;15(1):240-8.
261.
Ji P, Zhou Y, Yang Y, Wu J, Zhou H, Quan W, et al. Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/beta-catenin signaling. Theranostics. 2019;9(8):2209-23.
262.
Lee J, Shin KO, Kim Y, Cho J, Lim HW, Yoon SI, et al. Cathelicidin-related antimicrobial peptide regulates CD73 expression in mouse Th17 cells via p38. Cells. 2020;9(6):1561.
263.
Rabjerg M, Bjerregaard H, Halekoh U, Jensen BL, Walter S, Marcussen N. Molecular characterization of clear cell renal cell carcinoma identifies CSNK2A1, SPP1 and DEFB1 as promising novel prognostic markers. APMIS. 2016;124(5):372-83.
264.
Albrethsen J, Bøgebo R, Gammeltoft S, Olsen J, Winther B, Raskov H. Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1–3) in colon cancer serum and tumours: a biomarker study. BMC Cancer. 2005;5:8.
265.
Jeong D, Kim H, Kim D, Ban S, Oh S, Ji S, et al. Defensin alpha 6 (DEFA6) is a prognostic marker in colorectal cancer. Cancer Biomark. 2019;24(4):485-95.
266.
Xu N, Wang YS, Pan WB, Xiao B, Wen YJ, Chen XC, et al. Human alphadefensin-1 inhibits growth of human lung adenocarcinoma xenograft in nude mice. Mol Cancer Ther. 2008;7(6):1588-97.
267.
Wang YS, Li D, Shi HS, Wen YJ, Yang L, Xu N, et al. Intratumoral expression of mature human neutrophil peptide-1 mediates antitumor immunity in mice. Clin Cancer Res. 2009;15(22):6901-11.
268.
Li D, Qin Q, Wang XY, Shi HS, Luo M, Guo FC, et al. Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model. Oncol Rep. 2014;31(3):1287-95.
269.
Lundy FT, Orr DF, Gallagher JR, Maxwell P, Shaw C, Napier SS, et al. Identification and overexpression of human neutrophil alpha-defensins (human neutrophil peptides 1, 2 and 3) in squamous cell carcinomas of the human tongue. Oral Oncol. 2004;40(2):139-44.
270.
Semlali A, Al Amri A, Azzi A, Al Shahrani O, Arafah M, Kohailan M, et al. Expression and new exon mutations of the human Beta defensins and their association on colon cancer development. PLoS ONE. 2015;10(6):e0126868.
271.
Abiko Y, Suraweera AK, Nishimura M, Arakawa T, Takuma T, Mizoguchi I, et al. Differential expression of human beta-defensin 2 in keratinized and non-keratinized oral epithelial lesions; immunohistochemistry and in situ hybridization. Virchows Arch. 2001;438(3):248-53.
272.
Joly S, Compton LM, Pujol C, Kurago ZB, Guthmiller JM. Loss of human beta-defensin 1, 2, and 3 expression in oral squamous cell carcinoma. Oral Microbiol Immunol. 2009;24(5):353-60.
273.
Sawaki K, Mizukawa N, Yamaai T, Yoshimoto T, Nakano M, Sugahara T. High concentration of beta-defensin-2 in oral squamous cell carcinoma. Anticancer Res. 2002;22(4):2103-7.
274.
Donald CD, Sun CQ, Lim SD, Macoska J, Cohen C, Amin MB, et al. Cancer-specific loss of beta-defensin 1 in renal and prostatic carcinomas. Lab Invest. 2003;83(4):501-5.
275.
Sun CQ, Arnold R, Fernandez-Golarz C, Parrish AB, Almekinder T, He J, et al. Human beta-defensin-1, a potential chromosome 8p tumor suppressor: control of transcription and induction of apoptosis in renal cell carcinoma. Cancer Res. 2006;66(17):8542-9.
276.
Ling YM, Chen JY, Guo L, Wang CY, Tan WT, Wen Q, et al. Beta-defensin 1 expression in HCV infected liver/liver cancer: an important role in protecting HCV progression and liver cancer development. Sci Rep. 2017;7(1):13404.
277.
Bonamy C, Sechet E, Amiot A, Alam A, Mourez M, Fraisse L, et al. Expression of the human antimicrobial peptide beta-defensin-1 is repressed by the EGFR-ERK-MYC axis in colonic epithelial cells. Sci Rep. 2018;8(1):18043.
278.
Liu WJ, Liu XJ, Xu J, Li L, Li Y, Zhang SH, et al. EGFR-targeting, betadefensin-tailored fusion protein exhibits high therapeutic efficacy against EGFR-expressed human carcinoma via mitochondria-mediated apoptosis. Acta Pharmacol Sin. 2018;39(11):1777-86.
279.
Sun CQ, Arnold RS, Hsieh CL, Dorin JR, Lian F, Li Z, et al. Discovery and mechanisms of host defense to oncogenesis: targeting the β defensin-1 peptide as a natural tumor inhibitor. Cancer Biol Ther. 2019;20(6):774-86.
280.
Salem A, Almahmoudi R, Hagstrom J, Stark H, Nordstrom D, Salo T, et al. Human beta-defensin 2 expression in oral epithelium: potential therapeutic targets in oral lichen planus. Int J Mol Sci. 2019;20(7):1780.
281.
Li D, Wang W, Shi HS, Fu YJ, Chen X, Chen XC, et al. Gene therapy with beta-defensin 2 induces antitumor immunity and enhances local antitumor effects. Hum Gene Ther. 2014;25(1):63-72.
282.
Sun T, Luo Y, Wang M, Xie T, Yan H. Recombinant oncolytic vaccinia viruses expressing human β-defensin 2 enhance anti-tumor immunity. Mol Ther Oncolytics. 2019;13:49-57.
283.
Wang K, Wang JH, Baskaran H, Wang R, Jurevic R. Effect of human beta-defensin-3 on head and neck cancer cell migration using microfabricated cell islands. Head Neck Oncol. 2012;4:41.
284.
Hanaoka Y, Yamaguchi Y, Yamamoto H, Ishii M, Nagase T, Kurihara H, et al. In vitro and in vivo anticancer activity of human beta-defensin-3 and its mouse homolog. Anticancer Res. 2016;36(11):5999-6004.
285.
Xu D, Zhang B, Liao C, Zhang W, Wang W, Chang Y, et al. Human betadefensin 3 contributes to the carcinogenesis of cervical cancer via activation of NF-kappaB signaling. Oncotarget. 2016;7(46):75902-13.
286.
Gomez Hernandez MP, Bates AM, Starman EE, Lanzel EA, Comnick C, Xie XJ, et al. HBD3 induces PD-L1 expression on head and neck squamous cell carcinoma cell lines. Antibiotics (Basel). 2019;8(4):161.
287.
Strzelecka P, Czaplinska D, Sadej R, Wardowska A, Pikula M, Lesner A. Simplified, serine-rich theta-defensin analogues as antitumour peptides. Chem Biol Drug Des. 2017;90(1):52-63.
288.
Ye Z, Dong H, Li Y, Ma T, Huang H, Leong HS, et al. Prevalent homozygous deletions of type i interferon and defensin genes in human cancers associate with immunotherapy resistance. Clin Cancer Res. 2018;24(14):3299-308.
289.
Skalska J, Oliveira FD, Figueira TN, Mello EO, Gomes VM, McNaughton-Smith G, et al. Plant defensin PvD1 modulates the membrane composition of breast tumour-derived exosomes. Nanoscale. 2019;11(48):23366-81.
290.
Dong Z, Hu H, Yu X, Tan L, Ma C, Xi X, et al. Novel frog skin-derived peptide dermaseptin-PP for lung cancer treatment: in vitro/vivo evaluation and anti-tumor mechanisms study. Front Chem. 2020;8:476.
291.
Li X, Wang Y, Zou Z, Yang M, Wu C, Su Y, et al. OM-LV20, a novel peptide from odorous frog skin, accelerates wound healing in vitro and in vivo. Chem Biol Drug Des. 2018;91(1):126-36.
292.
Wu J, Yang J, Wang X, Wei L, Mi K, Shen Y, et al. A frog cathelicidin peptide effectively promotes cutaneous wound healing in mice. Biochem J. 2018;475(17):2785-99.
293.
Pfalzgraff A, Barcena-Varela S, Heinbockel L, Gutsmann T, Brandenburg K, Martinez-de-Tejada G, et al. Antimicrobial endotoxin-neutralizing peptides promote keratinocyte migration via P2X7 receptor activation and accelerate wound healing in vivo. Br J Pharmacol. 2018;175(17):3581-93.
294.
Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol. 2007;127(5):998-1008.
295.
Wang PH, Huang BS, Horng HC, Yeh CC, Chen YJ. Wound healing. J Chin Med Assoc. 2018;81(2):94-101.
296.
Takeo M, Lee W, Ito M. Wound healing and skin regeneration. Cold Spring Harb Perspect Med. 2015;5(1):a023267-71.
297.
Moravvej H, Memariani M, Memariani H, Robati RM, Gheisari M. Can antimicrobial peptides be repurposed as a novel therapy for keloids? Dermatology. 2021;237(2):293-5.
298.
Alencar-Silva T, Braga MC, Santana GOS, Saldanha-Araujo F, Pogue R, Dias SC, et al. Breaking the frontiers of cosmetology with antimicrobial peptides. Biotechnol Adv. 2018;36(8):2019-31.
299.
Yoo JH, Ho S, Tran DH, Cheng M, Bakirtzi K, Kukota Y, et al. Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitisassociated fibrosis. Cell Mol Gastroenterol Hepatol. 2015;1(1):55-74.
300.
Gauglitz GG, Bureik D, Zwicker S, Ruzicka T, Wolf R. The antimicrobial peptides psoriasin (S100A7) and koebnerisin (S100A15) suppress extracellular matrix production and proliferation of human fibroblasts. Skin Pharmacol Physiol. 2015;28(3):115-23.
301.
Yan Z, Wang D, An C, Xu H, Zhao Q, Shi Y, et al. The antimicrobial peptide YD attenuates inflammation via miR-155 targeting CASP12 during liver fibrosis. Acta Pharm Sin B. 2021;11(1):100-11.
302.
Ramos R, Silva JP, Rodrigues AC, Costa R, Guardao L, Schmitt F, et al. Wound healing activity of the human antimicrobial peptide LL37. Peptides. 2011;32(7):1469-76.
303.
Conlon JM, Mechkarska M, Abdel-Wahab YH, Flatt PR. Peptides from frog skin with potential for development into agents for type 2 diabetes therapy. Peptides. 2018;100:275-81.
304.
Zainab AJAA, Ashish N, Ragnath V. Salivary levels of antimicrobial peptides in chronic periodontitis patients with type 2 diabetes. J Int Acad Periodontol. 2019;21(1):36-44.
305.
Meguro S, Tomita M, Katsuki T, Kato K, Oh H, Ainai A, et al. Plasma antimicrobial peptide LL-37 level is inversely associated with HDL cholesterol level in patients with type 2 diabetes mellitus. Int J Endocrinol. 2014;2014:703696.
306.
Sun J, Furio L, Mecheri R, van der Does AM, Lundeberg E, Saveanu L, et al. Pancreatic β-cells limit autoimmune diabetes via an immunoregulatory antimicrobial peptide expressed under the influence of the gut microbiota. Immunity. 2015;43(2):304-17.
307.
Hu Z, Murakami T, Suzuki K, Tamura H, Kuwahara-Arai K, Iba T, et al. Antimicrobial cathelicidin peptide LL-37 inhibits the LPS/ATPinduced pyroptosis of macrophages by dual mechanism. PLoS ONE. 2014;9(1):e85765.
308.
Hu Z, Murakami T, Suzuki K, Tamura H, Reich J, Kuwahara-Arai K, et al. Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice. Int Immunol. 2016;28(5):245-53.
309.
Yoshimura T, McLean MH, Dzutsev AK, Yao X, Chen K, Huang J, et al. The antimicrobial peptide CRAMP is essential for colon homeostasis by maintaining microbiota balance. J Immunol. 2018;200(6):2174-85.
310.
Zhang M, Liang W, Gong W, Yoshimura T, Chen K, Wang JM. The critical role of the antimicrobial peptide LL-37/ CRAMP in protection of colon microbiota balance, mucosal homeostasis, anti-inflammatory responses, and resistance to carcinogenesis. Crit Rev Immunol. 2019;39(2):83-92.
311.
Rathinam VAK, Chan FK. Inflammasome, inflammation, and tissue homeostasis. Trends Mol Med. 2018;24(3):304-18.
312.
Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020;368(6494):973-80.
313.
Nguyen LT, Chau JK, Perry NA, de Boer L, Zaat SA, Vogel HJ. Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs. PLoS ONE. 2010;5(9):e12684.
314.
Schweizer F. Cationic amphiphilic peptides with cancer-selective toxicity. Eur J Pharmacol. 2009;625(1–3):190-4.
315.
Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug Discov Today. 2010;15(1–2):40-56.
316.
Li W, Separovic F, O’Brien-Simpson NM, Wade JD. Chemically modified and conjugated antimicrobial peptides against superbugs. Chem Soc Rev. 2021;50(8):4932-73.
317.
Malins LR. Peptide modification and cyclization via transition-metal catalysis. Curr Opin Chem Biol. 2018;46:25-32.
318.
Lei M, Jayaraman A, Van Deventer JA, Lee K. Engineering selectively targeting antimicrobial peptides. Annu Rev Biomed Eng. 2021;23:339-57.
319.
Schmidtchen A, Pasupuleti M, Malmsten M. Effect of hydrophobic modifications in antimicrobial peptides. Adv Colloid Interface Sci. 2014;205:265-74.
320.
Porter SL, Coulter SM, Pentlavalli S, Thompson TP, Laverty G. Self-assembling diphenylalanine peptide nanotubes selectively eradicate bacterial biofilm infection. Acta Biomater. 2018;77:96-105.
321.
Pedron CN, de Oliveira CS, da Silva AF, Andrade GP, da Silva Pinhal MA, Cerchiaro G, et al. The effect of lysine substitutions in the biological activities of the scorpion venom peptide VmCT1. Eur J Pharm Sci. 2019;136:104952.
322.
Torres MDT, Pedron CN, Higashikuni Y, Kramer RM, Cardoso MH, Oshiro KGN, et al. Structure-function-guided exploration of the antimicrobial peptide polybia-CP identifies activity determinants and generates synthetic therapeutic candidates. Commun Biol. 2018;1:221.
323.
Fjell CD, Hiss JA, Hancock RE, Schneider G. Designing antimicrobial peptides: form follows function. Nat Rev Drug Discov. 2011;11(1):37-51.
324.
Molhoek EM, van Dijk A, Veldhuizen EJ, Haagsman HP, Bikker FJ. Improved proteolytic stability of chicken cathelicidin-2 derived peptides by D-amino acid substitutions and cyclization. Peptides. 2011;32(5):875-80.
325.
Hilchie AL, Haney EF, Pinto DM, Hancock RE, Hoskin DW. Enhanced killing of breast cancer cells by a d-amino acid analog of the winter flounder-derived pleurocidin NRC-03. Exp Mol Pathol. 2015;99(3):426-34.
326.
Li Y, Liu T, Liu Y, Tan Z, Ju Y, Yang Y, et al. Antimicrobial activity, membrane interaction and stability of the D-amino acid substituted analogs of antimicrobial peptide W3R6. J Photochem Photobiol B. 2019;200:111645.
327.
Chen HL, Su PY, Shih C. Improvement of in vivo antimicrobial activity of HBcARD peptides by D-arginine replacement. Appl Microbiol Biotechnol. 2016;100(21):9125-32.
328.
Zhang L, Carmichael R. Short antimicrobial lipopeptides. WO2013142088 A1. 2013.
329.
Eckert Randal H, Yarbrough Daniel K, Shi W, Anderson Maxwell H, Qi F, He J, et al. Selectively targeted antimicrobial peptides and the use thereof. WO2008030988 A2. 2008.
330.
Gunasekera S, Muhammad T, Strömstedt AA, Rosengren KJ, Göransson U. Backbone cyclization and dimerization of LL-37-derived peptides enhance antimicrobial activity and proteolytic stability. Front Microbiol. 2020;11:168.
331.
Ting DSJ, Beuerman RW, Dua HS, Lakshminarayanan R, Mohammed I. Strategies in translating the therapeutic potentials of host defense peptides. Front Immunol. 2020;11:983.
332.
Dathe M, Nikolenko H, Klose J, Bienert M. Cyclization increases the antimicrobial activity and selectivity of arginine- and tryptophancontaining hexapeptides. Biochemistry. 2004;43(28):9140-50.
333.
Thomsen TT, Mendel HC, Al-Mansour W, Oddo A, Lobner-Olesen A, Hansen PR. Analogues of a cyclic antimicrobial peptide with a flexible linker show promising activity against Pseudomonas aeruginosa and Staphylococcus aureus. Antibiotics (Basel). 2020;9(7):366.
334.
Scudiero O, Nigro E, Cantisani M, Colavita I, Leone M, Mercurio FA, et al. Design and activity of a cyclic mini-beta-defensin analog: a novel antimicrobial tool. Int J Nanomed. 2015;10:6523-39.
335.
Moiola M, Memeo MG, Quadrelli P. Stapled peptides—a useful improvement for peptide-based drugs. Molecules. 2019;24(20):3654.
336.
Hirano M, Saito C, Yokoo H, Goto C, Kawano R, Misawa T, et al. Development of antimicrobial stapled peptides based on magainin 2 sequence. Molecules. 2021;26(2):444.
337.
Grassi L, Maisetta G, Esin S, Batoni G. Combination strategies to enhance the efficacy of antimicrobial peptides against bacterial biofilms. Front Microbiol. 2017;8:2409.
338.
Almaaytah A, Qaoud MT, Abualhaijaa A, Al-Balas Q, Alzoubi KH. Hybridization and antibiotic synergism as a tool for reducing the cytotoxicity of antimicrobial peptides. Infect Drug Resist. 2018;11:835-47.
339.
Wang C, Yang C, Chen YC, Ma L, Huang K. Rational design of hybrid peptides: a novel drug design approach. Curr Med Sci. 2019;39(3):349-55.
340.
Fox MA, Thwaite JE, Ulaeto DO, Atkins TP, Atkins HS. Design and characterization of novel hybrid antimicrobial peptides based on cecropin A, LL-37 and magainin II. Peptides. 2012;33(2):197-205.
341.
David AA, Park SE, Parang K, Tiwari RK. Antibiotics-peptide conjugates against multidrug-resistant bacterial pathogens. Curr Top Med Chem. 2018;18(22):1926-36.
342.
Schnaider L, Rosenberg A, Kreiser T, Kolusheva S, Gazit E, Berman J. Peptide self-assembly is linked to antibacterial, but not antifungal, activity of histatin 5 derivatives. mSphere. 2020;5(2):e00021-e120.
343.
Nel AE, Mädler L, Velegol D, Xia T, Hoek EM, Somasundaran P, et al. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater. 2009;8(7):543-57.
344.
Hancock RE, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006;24(12):1551-7.
345.
Carratalá JV, Serna N, Villaverde A, Vázquez E, Ferrer-Miralles N. Nanostructured antimicrobial peptides: the last push towards clinics. Biotechnol Adv. 2020;44:107603.
346.
Umerska A, Cassisa V, Matougui N, Joly-Guillou ML, Eveillard M, Saulnier P. Antibacterial action of lipid nanocapsules containing fatty acids or monoglycerides as co-surfactants. Eur J Pharm Biopharm. 2016;108:100-10.
347.
Radaic A, de Jesus MB, Kapila YL. Bacterial anti-microbial peptides and nano-sized drug delivery systems: the state of the art toward improved bacteriocins. J Control Release. 2020;321:100-18.
348.
Lam SJ, O’Brien-Simpson NM, Pantarat N, Sulistio A, Wong EHH, Chen YY, et al. Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers. Nat Microbiol. 2016;1(11):16162.
349.
Falciani C, Zevolini F, Brunetti J, Riolo G, Gracia R, Marradi M, et al. Antimicrobial peptide-loaded nanoparticles as inhalation therapy for Pseudomonas aeruginosa infections. Int J Nanomedicine. 2020;15:1117-28.
350.
Taylor EN, Webster TJ. The use of superparamagnetic nanoparticles for prosthetic biofilm prevention. Int J Nanomed. 2009;4:145-52.
351.
Liu Y, Sun Y, Li S, Liu M, Qin X, Chen X, et al. Tetrahedral framework nucleic acids deliver antimicrobial peptides with improved effects and less susceptibility to bacterial degradation. Nano Lett. 2020;20(5):3602-10.
352.
Rajchakit U, Sarojini V. Recent developments in antimicrobial-peptideconjugated gold nanoparticles. Bioconjug Chem. 2017;28(11):2673-86.
353.
Nyström L, Strömstedt AA, Schmidtchen A, Malmsten M. Peptideloaded microgels as antimicrobial and anti-inflammatory surface coatings. Biomacromol. 2018;19(8):3456-66.
354.
Martin-Serrano Á, Gómez R, Ortega P, de la Mata FJ. Nanosystems as vehicles for the delivery of antimicrobial peptides (AMPs). Pharmaceutics. 2019;11(9):448.
355.
Teixeira MC, Carbone C, Sousa MC, Espina M, Garcia ML, Sanchez-Lopez E, et al. Nanomedicines for the delivery of antimicrobial peptides (AMPs). Nanomaterials (Basel). 2020;10(3):560.
356.
Dusinska M, Tulinska J, El Yamani N, Kuricova M, Liskova A, Rollerova E, et al. Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: new strategies for toxicity testing? Food Chem Toxicol. 2017;109(Pt 1):797-811.
357.
Makowski M, Silva ÍC, Pais do Amaral C, Gonçalves S, Santos NC. Advances in lipid and metal nanoparticles for antimicrobial peptide delivery. Pharmaceutics. 2019;11(11):588.
358.
Kim GC, Cheon DH, Lee Y. Challenge to overcome current limitations of cell-penetrating peptides. Biochim Biophys Acta Proteins Proteom. 2021;1869(4):140604.
359.
Bahnsen JS, Franzyk H, Sayers EJ, Jones AT, Nielsen HM. Cell-penetrating antimicrobial peptides—prospectives for targeting intracellular infections. Pharm Res. 2015;32(5):1546-56.
360.
Lee H, Lim SI, Shin SH, Lim Y, Koh JW, Yang S. Conjugation of cellpenetrating peptides to antimicrobial peptides enhances antibacterial activity. ACS Omega. 2019;4(13):15694-701.
361.
Hansen A, Schäfer I, Knappe D, Seibel P, Hoffmann R. Intracellular toxicity of proline-rich antimicrobial peptides shuttled into mammalian cells by the cell-penetrating peptide penetratin. Antimicrob Agents Chemother. 2012;56(10):5194-201.
362.
Budagavi DP, Chugh A. Antibacterial properties of Latarcin 1 derived cell-penetrating peptides. Eur J Pharm Sci. 2018;115:43-9.
363.
Drexelius M, Reinhardt A, Grabeck J, Cronenberg T, Nitsche F, Huesgen PF, et al. Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity. Biochem J. 2021;478(1):63-78.
364.
Hao X, Yan Q, Zhao J, Wang W, Huang Y, Chen Y. TAT Modification of alpha-helical anticancer peptides to improve specificity and efficacy. PLoS ONE. 2015;10(9):e0138911.
365.
Mathur H, Field D, Rea MC, Cotter PD, Hill C, Ross RP. Bacteriocinantimicrobial synergy: a medical and food perspective. Front Microbiol. 2017;8:1205.
366.
Lee H, Lee DG. Novel approaches for efficient antifungal drug action. J Microbiol Biotechnol. 2018;28(11):1771-81.
367.
Dosler S, Mataraci E. In vitro pharmacokinetics of antimicrobial cationic peptides alone and in combination with antibiotics against methicillin resistant Staphylococcus aureus biofilms. Peptides. 2013;49:53-8.
368.
Mataraci E, Dosler S. In vitro activities of antibiotics and antimicrobial cationic peptides alone and in combination against methicillin-resistant Staphylococcus aureus biofilms. Antimicrob Agents Chemother. 2012;56(12):6366-71.
369.
Li S, She P, Zhou L, Zeng X, Xu L, Liu Y, et al. High-throughput identification of antibacterials against Pseudomonas aeruginosa. Front Microbiol. 2020;11:591426.
370.
Chen Y, Wu J, Cheng H, Dai Y, Wang Y, Yang H, et al. Anti-infective effects of a fish-derived antimicrobial peptide against drug-resistant bacteria and its synergistic effects with antibiotic. Front Microbiol. 2020;11:602412.
371.
Lin L, Nonejuie P, Munguia J, Hollands A, Olson J, Dam Q, et al. Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens. EBioMedicine. 2015;2(7):690-8.
372.
Vriens K, Cools TL, Harvey PJ, Craik DJ, Spincemaille P, Cassiman D, et al. Synergistic activity of the plant defensin HsAFP1 and caspofungin against Candida albicans biofilms and planktonic cultures. PLoS ONE. 2015;10(8):e0132701.
373.
Casciaro B, Loffredo MR, Luca V, Verrusio W, Cacciafesta M, Mangoni ML. Esculentin-1a derived antipseudomonal peptides: limited induction of resistance and synergy with aztreonam. Protein Pept Lett. 2018;25(12):1155-62.
374.
Magana M, Pushpanathan M, Santos AL, Leanse L, Fernandez M, Ioannidis A, et al. The value of antimicrobial peptides in the age of resistance. Lancet Infect Dis. 2020;20(9):e216-30.
375.
Glattard E, Salnikov ES, Aisenbrey C, Bechinger B. Investigations of the synergistic enhancement of antimicrobial activity in mixtures of magainin 2 and PGLa. Biophys Chem. 2016;210:35-44.
376.
Zerweck J, Strandberg E, Kukharenko O, Reichert J, Burck J, Wadhwani P, et al. Molecular mechanism of synergy between the antimicrobial peptides PGLa and magainin 2. Sci Rep. 2017;7(1):13153.
377.
Ma W, Sun S, Li W, Zhang Z, Lin Z, Xia Y, et al. Individual roles of peptides PGLa and magainin 2 in synergistic membrane poration. Langmuir. 2020;36(26):7190-9.
378.
Remington JM, Liao C, Sharafi M, Ste Marie EJ, Ferrell JB, Hondal RJ, et al. Aggregation state of synergistic antimicrobial peptides. J Phys Chem Lett. 2020;11(21):9501-6.
379.
Ilyas H, Kim J, Lee D, Malmsten M, Bhunia A. Structural insights into the combinatorial effects of antimicrobial peptides reveal a role of aromatic-aromatic interactions in antibacterial synergism. J Biol Chem. 2019;294(40):14615-33.
380.
Zhao X, Zhen Z, Wang X, Guo N. Synergy of a combination of nisin and citric acid against Staphylococcus aureus and Listeria monocytogenes. Food Addit Contam A Chem Anal Control Expo Risk Assess. 2017;34(12):2058-68.
381.
Ahn KB, Kim AR, Kum KY, Yun CH, Han SH. The synthetic human beta-defensin-3 C15 peptide exhibits antimicrobial activity against Streptococcus mutans, both alone and in combination with dental disinfectants. J Microbiol. 2017;55(10):830-6.
382.
Badaoui Najjar M, Kashtanov D, Chikindas ML. Epsilon-poly-L-lysine and nisin A act synergistically against Gram-positive food-borne pathogens Bacillus cereus and Listeria monocytogenes. Lett Appl Microbiol. 2007;45(1):13-8.
383.
Namivandi-Zangeneh R, Wong EHH, Boyer C. Synthetic antimicrobial polymers in combination therapy: tackling antibiotic resistance. ACS Infect Dis. 2021;7(2):215-53.
384.
Tian J, Zhang J, Yang J, Du L, Geng H, Cheng Y. Conjugated polymers act synergistically with antibiotics to combat bacterial drug resistance. ACS Appl Mater Interfaces. 2017;9(22):18512-20.
385.
Thappeta KRV, Vikhe YS, Yong AMH, Chan-Park MB, Kline KA. Combined efficacy of an antimicrobial cationic peptide polymer with conventional antibiotics to combat multidrug-resistant pathogens. ACS Infect Dis. 2020;6(5):1228-37.
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doi: 10.1186/s40779-021-00343-2
  • Online Date：2025-12-22
  • Published：2022-04-10
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Affiliations
History
Funding
grants from the National Natural Science Foundation of China(81770176)
special support plan for Zhejiang Province High-Level Talents(2019R52011)
Affiliations
    1Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou 310018, China
    2Department of Oncology, The 903rd Hospital of PLA, Hangzhou 310013, China
    3Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd. South, San Francisco, CA 94158, USA
    4Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia
    5Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia

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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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