Home Journals Articles Updates About
CN
image
收藏切换
Towards a better understanding of antimicrobial resistance dissemination: what can be learnt from studying model conjugative plasmids?
收藏切换
PDF
Zhen Shen1, 2, Christoph M. Tang1, Guang-Yu Liu1, *
Military Medical Research | 2022, 9(5) : 592 - 602
Less
收藏切换
Military Medical Research | 2022, 9(5): 592-602
• REVIEW •
Towards a better understanding of antimicrobial resistance dissemination: what can be learnt from studying model conjugative plasmids?
Full
Zhen Shen1, 2, Christoph M. Tang1, Guang-Yu Liu1, *
Affiliations
  • 1Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
  • 2Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Published: 2022-10-10 doi: 10.1186/s40779-021-00362-z
Outline
收藏切换

Bacteria can evolve rapidly by acquiring new traits such as virulence, metabolic properties, and most importantly, antimicrobial resistance, through horizontal gene transfer (HGT). Multidrug resistance in bacteria, especially in Gram-negative organisms, has become a global public health threat often through the spread of mobile genetic elements. Conjugation represents a major form of HGT and involves the transfer of DNA from a donor bacterium to a recipient by direct contact. Conjugative plasmids, a major vehicle for the dissemination of antimicrobial resistance, are selfish elements capable of mediating their own transmission through conjugation. To spread to and survive in a new bacterial host, conjugative plasmids have evolved mechanisms to circumvent both host defense systems and compete with co-resident plasmids. Such mechanisms have mostly been studied in model plasmids such as the F plasmid, rather than in conjugative plasmids that confer antimicrobial resistance (AMR) in important human pathogens. A better understanding of these mechanisms is crucial for predicting the flow of antimicrobial resistance-conferring conjugative plasmids among bacterial populations and guiding the rational design of strategies to halt the spread of antimicrobial resistance. Here, we review mechanisms employed by conjugative plasmids that promote their transmission and establishment in Gram-negative bacteria, by following the life cycle of conjugative plasmids.

Horizontal gene transfer  /  Antimicrobial resistance  /  Conjugative plasmids  /  Type IV secretion system  /  Restriction-modification systems  /  SOS response  /  Entry exclusion  /  Fertility inhibition
Zhen Shen, Christoph M. Tang, Guang-Yu Liu. Towards a better understanding of antimicrobial resistance dissemination: what can be learnt from studying model conjugative plasmids?[J]. Military Medical Research, 2022 , 9 (5) : 592 -602 . DOI: 10.1186/s40779-021-00362-z
Full Text
Less
Background
Less
Horizontal gene transfer (HGT) is defined as the intra-generational sharing of genetic material. HGT represents one of the most important evolutionary forces in bacteria as it enables rapid adaptation to changing environmental pressures through the acquisition of new traits such as virulence, metabolic pathways, and antimicrobial resistance (AMR) encoded by mobile genetic elements (MGEs)[1-5].
Among the MGE-conferred traits, AMR is of particular importance as it has been declared by WHO as one of the top 10 global public health threats facing humanity[6]. According to the O’Neill report, AMR accounts for at least 700,000 deaths globally every year and this figure is projected to reach 10 million by 2050. Moreover, the lost global production due to AMR between now and 2050 is predicted to be 100 trillion USD if no action is taken[7]. Nosocomial infections are a major concern posed by AMR in which patients with compromised immune systems are extremely vulnerable to bacterial infection[8]. Although most bacterial pathogens remain susceptible to the majority of clinically used antimicrobial agents such as carbapenems and amikacin, a few of them have developed extensive resistance to the action of antibiotics. Among these multi-resistant bacteria, “the ESKAPE pathogens”, which consist of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), Pseudomonas aeruginosa (P. aeruginosa), and Enterobacter species, constitute the biggest threat to human health as they are responsible for the majority of nosocomial infections[8,9].
Mechanistically, many ESKAPE pathogens, especially K. pneumoniae and Enterobacter species, acquire AMR mainly through the process of conjugation, which involves the concerted action of a mating pair formation (MPF) system and a matching DNA processing system, ultimately resulting in the transfer of one strand of DNA (the T-strand) from a donor cell to a recipient in which the complementary DNA strand is synthesized subsequently[10-12].
The most concerning resistance genes in clinical practice, such as mcr-1, blaKPC and blaNDM, are all encoded by conjugative plasmids (CPs). CPs encode all genes required for their own transfer through mating and are particularly important for human and animal health, given their potential as vehicles to spread AMR[3]. To date, mcr-1, blaKPC and blaNDM have been identified in numerous countries across five continents[13-15]. MCR-1 belongs to the phosphoethanolamine transferase family and can help to modify the structure of lipid A, thus conferring resistance to colistin[16]. It is usually harbored by the epidemic IncI2 and IncX4 CPs and has mainly been identified in Escherichia coli (E. coli)[17]. KPC and NDM are the most prevalent carbapenemases and could hydrolyze almost all beta-lactams; blaKPC and blaNDM, genes encoding KPC and NDM, are frequently detected in K. pneumoniae and E. coli and are mainly harbored by IncFII, IncFII/IncR, IncF and IncX3 CPs[14,15].
Despite their clinical significance, how AMR-harboring CPs mediate their conjugative transfer and establish themselves in new bacterial hosts remain largely unexplored, especially for those epidemic IncI2, IncX3 and IncX4 CPs. Of note, AMR-harboring CPs from the IncF and IncFII families encode conjugative machinery and accessory proteins which are closely related to the well-studied model CPs, such as the F, R1 and the R100 plasmid[18,19]. Therefore, here we summarize the molecular mechanisms by which CP-borne elements from Gram-negative bacteria facilitate conjugative transfer and become established in their new host, mainly using model CPs as examples. This review also attempts to shed light on the dissemination of AMR as the MPF systems of certain families of AMR-harboring CPs, such as the carbapenemase-encoding IncF and IncFII CPs, are highly homologous to those from model CPs such as the F and the R1 plasmid. However, extrapolating knowledge gained from studying model CPs to clinical AMR-harboring plasmids has a limit as the latter belong to a wide range of incompatibility groups, each of which may employ different strategies for host colonization and establishment. Proteins that are directly involved in MPF and conjugative DNA processing are not discussed here as they are reviewed in detail elsewhere[20-24]. For the convenience of discussion, we split the life cycle of CPs into three steps: before, during, and after conjugation.
Before conjugation
Less
CPs possess transfer genes that encode all factors necessary for the assembly of the MPF system including the conjugative pilus and the type IV secretion system (T4SS), as well as the relaxosome components required for the processing of plasmid DNA prior to transfer. The transfer genes are usually clustered in the tra region of CPs, and expression of tra region can impose significant fitness costs on the host bacterium[25]. Therefore, the expression of tra genes on CPs is tightly regulated. For instance, in F-like plasmids, the tra operon is normally repressed [26]. PY, the primary promoter of the tra operon is under the direct control of a transcription activator, TraJ[27,28]; TraJ is post-transcriptionally repressed by the fertility inhibition system FinOP[29]. FinP is an antisense RNA that binds to the 5’ untranslated region (UTR) of traJ mRNA, masking the ribosome binding site and inhibiting TraJ translation[30,31]. FinO is an RNA chaperone that protects the FinP antisense RNA from RNase E degradation, thereby stabilizing the FinP-traJ mRNA duplex[29,32,33]. The finOP has also been spotted on the epidemic IncFII/IncR and IncFII KPC plasmid, which shares 95% sequence similarity with the finOP on the R1 plasmid[18], suggesting that it might also be involved in the regulation of the tra operon.
Conjugation imposes significant stress on the donor. Expression and assembly of a functional MPF system, such as the sex pilus from the F plasmid, triggers the cpxAR and σE stress response pathways in E. coli and leads to sensitivity to bile salts[34,35]. To alleviate the fitness costs in donor cells during conjugation, TraR, a transcription factor encoded on the tra operon on the F plasmid, directly activates the σE extracytoplasmic stress pathway independent of the DegS/RseA signal transduction cascade, upregulating periplasmic proteases and chaperones to relieve the periplasmic stress following biosynthesis of the sex pilus[36].
During conjugation
Less
Early expression of leading region genes
Conjugative DNA transfer is initiated at a specific sequence on a CP, the oriT, which is recognized and nicked by the relaxase. The leading region of CPs is the sequence adjacent to the oriT and hence is the first to be transferred into the recipient cell (Fig. 1)[37,38]. The leading region encodes proteins that play important roles in facilitating conjugative transfer. For instance, the leading region of the F and the R1 plasmid is a highly conserved 13–16 kb region that encodes for at least eight proteins[18,38]. A conserved leading region has also been spotted on the epidemic IncFII/IncR and IncFII KPC plasmid, which is closely related to the R1 plasmid and shares about 90% sequence similarity[18]. Besides, for IncFII/IncR plasmid, it also has another leading region with IncR origin. How these two leading regions work together to facilitate conjugative transfer still needs further investigation.
Leading region genes can be expressed rapidly and transiently following conjugation from the partially transferred single stranded plasmid DNA in the recipient cell before its conversion into dsDNA, a phenomenon termed zygotic induction[39]. Mechanistically, zygotic induction requires Frpo-type promoters for single-strand initiation of DNA replication[40]. The F plasmid Frpo is a 328 bp sequence that adopts a stem-loop structure containing the -10 and -35 boxes required for binding of RNA polymerase and the synthesis of RNA primers[38]. Consistent with this, expression of leading region genes was shown to be driven by Frpo-like sequences in vivo[37,41]. Furthermore, leading region genes whose early expression requires Frpo-like sequences are widespread in conjugative plasmids; their roles in promoting successful conjugation are discussed below.
ssDNA binding proteins
Bacterial single-stranded DNA (ssDNA) binding (SSB) proteins typically consist of two domains: a ssDNA-binding oligonucleotide/oligosaccharide-binding (OB) domain and a structurally dynamic amphipathic C-terminal tail (SSB-Ct)[42,43]. SSB proteins oligomerize through their OB domains to become active[42,44]. For instance, each E. coli SSB protein has a single OB domain and becomes functional as a homotetramer[42-45]. SSB proteins diffuse on ssDNA as a sliding platform via reptation and form liquid–liquid phase separated condensates[46,47]. SSB proteins are more than mere ssDNA binders, and act as bridges to recruit a repertoire of proteins to ssDNA through the SSB-Ct[45,48]. These proteins are involved in various aspects of DNA metabolism including replication, repair, and recombination[49-51].
In the context of conjugation, upon entry of the plasmid into the recipient cell, ssDNA needs to be rapidly coated with SSB proteins. Although the recipient cell encodes its own SSB protein, conjugative plasmids frequently encode their own SSB in the leading region to ensure rapid and abundant expression, allowing protection of ssDNA from enzymatic degradation and facilitating conversion of the T-strand into dsDNA[52].
SSB proteins can also be part of the arsenal of CPs to subvert host defense. In a recent study using Tn-seq, Roy et al.[53], identified an hde (host defense evasion) locus critical for the multidrug resistance-conferring IncC plasmid pVCR94. This locus enables the plasmid to paratisize Vibrio cholerae possessing a heterologous type I CRISPR-Cas locus from E. coli. The hde locus contains five ORFs (vcrx089–vcrx093), with vcrx089 and vcrx090 encoding proteins that increase resistance against type I restriction-modification (R-M) systems, while vcrx091, vcrx091, and vcxr093 encode an SSB, a single-strand annealing recombinase, and double-strand exonuclease related to Redβ and λExo of bacteriophage λ, respectively. These three proteins work in concert to repair CRISPR-Cas-mediated DNA double-strand breaks via homologous recombination between short sequence repeats in the plasmid[53].
PsiB
During conjugation, plasmids enter the recipient cell in the form of ssDNA which induces an SOS response in E. coli[54-56]. Mechanistically, binding of RecA to single-stranded plasmid DNA leads to the formation of a RecA nucleofilament that catalyzes the auto-proteolytic cleavage of the LexA repressor. Cleavage of LexA de-represses genes belonging to the SOS regulon, which comprises around 40 genes in E. coli[55,57]. Among the genes induced by the SOS response, several impede the conjugative transfer of plasmids. For instance, the division inhibitor SulA causes growth arrest, cell filamentation, and even cell death[58], leading to abortive CP transfer. Moreover, components that constitute DNA polymerase IV and V could introduce mutations into the transferred ssDNA[55]. To counteract the detrimental effects of the SOS response, conjugative plasmids belonging to different incompatibility groups, including the F plasmid, encode plasmid SOS inhibition (PsiB)[59]. Residing on the leading region, psiB expression also is subject to zygotic induction in IncF and IncI CPs[41,60]. In addition to that, PsiB from IncFV plasmid pED208, along with SSB, was shown to be translocated directly through T4SS to suppress SOS response in the recipient[61]. PsiB binds directly to RecA, preventing nucleoprotein filament formation on ssDNA; this effect is more pronounced when ssDNA is bound by SSB such as during conjugal transfer[62]. PsiB-RecA interaction also prevents LexA autocleavage and hence the SOS response to ssDNA[62]. As PsiB-mediated RecA inhibition is based on PsiB-RecA binding, the inhibitory effect of PsiB varies in a species-specific manner[54].
Anti-restriction-modification system proteins
Bacterial R-M systems are prokaryotic ‘innate immune systems’ that degrade exogenous DNA, in the form of phages and plasmids, entering the cell. R-M systems are typically comprised of a restriction endonuclease (REase) and a cognate methyltransferase (MTase). REases recognize and cleave unmethylated dsDNA of a specific sequence, whilst their cognate MTases protect DNA from REase cleavage by methylating adenine or cytosine residues within the recognized sequence. Differences in methylation allow R-M systems to discriminate invading DNA from host DNA to achieve targeted degradation[63-66].
As R-M systems act as a barrier against HGT, CPs have evolved several strategies to avoid restriction upon entry into recipient cells[66,67]. The first plasmid anti-restriction system ArdA (alleviation of restriction of DNA) system was discovered in the IncI1 plasmid ColIbP-9[68]. Of note, similar to PsiB, ArdA is encoded on the leading region of ColIbP-9 and is expressed by a Frpo-like promoter during conjugation before the incoming T-stand is converted into dsDNA[41].
ArdA proteins largely act on the REase of type I R-M systems but leave their modification activity largely unperturbed[69]. The crystal structure of ArdA reveals that ArdA dimers adopt an elongated curved cylindrical structure with regularly spaced helical grooves[70]. The surface of the ArdA dimer has a helical distribution of aspartate and glutamate residues, with the protein mimicking a 42-bp sequence of B-form DNA[70]. Later, a Cryo-EM structure of the type I R-M system EcoR124I complex demonstrated that type I R-M systems coordinate and regulate their endonuclease, methyltransferase, and translocase activities in a single complex by transitioning between different structural conformations[71]. Moreover, a structure of the EcoR124I in complex with ArdA reveals that ArdA does indeed bind DNA as a dimer, and intriguingly ArdA inhibits the function of the R-M complex without blocking its conformational transitions[71].
ArdB belongs to another family of proteins that antagonize type I R-M systems and was first identified from the IncN group conjugative plasmid pKM101[72]. ArdB and ArdA are encoded on the leading region of pKM101 and their expression was controlled by ArdK and ArdR, two regulatory proteins encoded by the leading region[72]. Similar to ArdA, ArdB and its homologue KlcA specifically inhibit type I restriction in vivo, even though they have no activity against type I REase EcoKI in vitro[72,73], indicating that the mechanism of REase inhibition that ArdB employs is unlikely to be direct, unlike ArdA[71,73]. Consistent with this, the nuclear magnetic resonance (NMR) structure of KlcA from pBP136, an IncP-1b plasmid from Bordetella pertussis, demonstrated that KlcA has a novel fold, which does not appear to be a DNA mimic[73,74]. Plasmids carrying blaKPC-2 are the primary cause of carbapenem resistance in K. pneumoniae, and often harbor klcAHS, a gene that encodes an ArdB homologue[75,76]. Moreover, KlcAHS was shown to increase transformation efficiency in E. coli encoding type I R-M systems belonging to different subclasses, suggesting KlcAHS plays an important role in the dissemination of carbapenem resistance in K. pneumoniae[75,76].
ArdC, the third type of restriction alleviation protein, was first identified in the IncW plasmid pSa and later also studied in another IncW plasmid R388[77,78]. ArdC is required for the conjugative transfer of R388 from E. coli to Pseudomonas putida (P. putida) by targeting a type I R-M system in the recipient, extending the broad host range of R388[78]. ArdC shares low identity with ArdA and ArdB, but it has 38% identity with the N-terminal portion of TraC1 primase encoded by the IncP plasmid RP4[77]. During conjugation, TraC1 is co-transferred with RP4 into the recipient cell, where it acts to generate RNA primers to initiate complementary strand synthesis of the T-strand[79]. Since the N-terminal portion of TraC1 is necessary for the conjugative transfer of TraC1, ArdC was also proposed to be transferred into the recipient and protect the T-strand[77]. The crystal structure of ArdC reveals that it consists of an N-terminal ssDNA-binding domain and a C-terminal metalloprotease domain[78]. Intriguingly, the metalloprotease activity of ArdC is dispensable for R388 conjugation into P. putida with the substrate of the metalloprotease domain unknown[78].
In contrast to R-M systems that consist of a coupled MTase and REase, many MTases lack cognate REase partners and are hence known as orphan MTases[80,81]. The first genome-wide methylome study in bacteria by single-molecule real-time (SMRT) sequencing identified M.EcoGIX, an orphan MTase encoded on a conjugative plasmid pESBL in E. coli O104:H4[82]. M.EcoGIX modifies adenine in a wide range of sequence contexts, and more surprisingly, it methylates only one strand of dsDNA[82]. Later, M.EcoGIX was shown to protect pESBL from restriction by R-M systems in a range of E. coli hosts during conjugation[83]. M.EcoGIX homologues are present on conjugative plasmids belonging to different incompatibility groups[83-85], in which M.EcoGIX encoded on pESBL from E. coli O104:H4 and M.BceJIII encoded on pBCG2315 of Burkholderia cenocepacia J2315 were characterized by Formenkov et al.[86]. It was shown that both MTases are encoded on the leading region and expressed early during conjugation, and they work in concert with DNA polymerase I to methylate the T-strand, protecting the plasmid from R-M systems during the conversion of the T-strand into DNA duplex[86].
After conjugation
Less
Successful conjugation does not guarantee the successful establishment and long-term persistence of CPs in their new hosts. Although many CPs encode beneficial traits such as AMR, carriage of CPs imposes a fitness cost on their hosts in the absence of selection for beneficial traits. As a result, models predict that costly CPs will be removed from the population over time by purifying selection or that CP-borne beneficial genes should be integrated into the host chromosome. However, long-term bacteria-plasmid co-culture experiments have shown that plasmids can persist for long periods, even in the absence of positive selection[87,88]. This discrepancy between theoretical predictions and experimental observations constitutes “the plasmid paradox”[89-91]. To achieve this higher-than-predicted stability, CPs have evolved multiple mechanisms that promote their persistence at the population level. Among these mechanisms, partitioning systems and toxin-antitoxin systems are best characterized examples, which promote segregation of plasmids into daughter cells during cell division and eliminate daughter cells that fail to inherit plasmids after cell division, respectively. These systems will not be discussed further as they have been extensively reviewed elsewhere[92-96]. Instead, this review aims to focus on two mechanisms by which CPs employ to enhance their evolutionary fitness by manipulating subsequent conjugation events in their new hosts: entry exclusion and fertility inhibition.
Entry exclusion
Entry exclusion refers to the formation of a barrier to the horizontal transfer of CPs between bacteria carrying closely related conjugation machineries. Entry exclusion is an essential feature of CPs, and bacterial cells harboring these plasmids become poor recipients during further rounds of conjugation (Fig. 2)[97,98]. For the F plasmid, this property is conferred by the entry exclusion locus (traST) at the distal end of the tra operon[99]. TraT is highly expressed on the outer membrane and acts to destabilize mating aggregates[100]. TraS, an inner membrane protein, interacts with TraG, a protein crucial for mating pair stabilization[101]. TraG synthesized in the donor cell was suggested to be translocated into the recipient and become quenched by TraS, resulting in blocked transfer of the T-strand[102]. The precise mechanisms of action of these exclusion factors remain incompletely understood.
The physiological importance of entry exclusion is highlighted by the failure to isolate F plasmids carrying traS and traT mutations by chemical mutagenesis[103]. F plasmid mutants which are proficient for transfer but exclusion-deficient are unstable under normal growth conditions, suggesting that entry exclusion can be essential for the stability of a CP. Additionally, excessive rounds of conjugation lead to bacterial death, due to the cell permeability induced by extensive damage in the cell membrane of the recipient[104]. This could be significantly inhibited by entry exclusion, which prevents conjugation and helps to establish immunity to cell damage.
Fertility inhibition
To increase the probability of their long-term evolutionary success, CPs need to minimize the fitness costs they impose on their host resulting from unnecessary expression of the conjugation machinery, which expends a significant amount of cellular resources and renders the host bacterium vulnerable to predation by sex-pili targeting phages[105]. Fertility inhibition (FI) systems are ubiquitously present on CPs belonging to different incompatibility groups and inhibit the conjugal transfer of CPs[106-108]. The targets of FI systems can vary from CPs that encode the FI systems themselves to other CPs co-resident in the same bacterium[106]. Although the mechanisms by which FI systems block conjugation are poorly understood, current knowledge already shows that different FI systems target different steps of the conjugation process (Fig. 2)[106,107].
First, as exemplified by the FinOP system, FI systems can impair the expression of genes encoding MPF systems at multiple levels. For instance, the FinQ and FinW systems inhibit transfer of the F plasmid by targeting transcription of F plasmid-encoded T4SS. FinW, encoded by IncFI plasmids such as R455, represses transcription of TraM[109], an essential component of the F plasmid relaxosome[110,111]. On the other hand, FinQ, encoded by IncI1 plasmids such as R820a, terminates transcription of the tra operon at multiple sites in a Rho-independent fashion[112]. Consistent with these FI systems targeting transcription of transfer genes, long-term bacteria-plasmid co-culture experiments demonstrated that down-regulation of transfer genes expression could ameliorate the cost-of-carriage of CPs[91].
FI systems can also function without regulating expression of the conjugative machinery. Osa, encoded by the IncW plasmid pSa, inhibits the delivery of oncogenic T-DNA encoded by the Ti plasmid of Agrobacterium tumefaciens (A. tumefaciens) to plant cells[113]. Osa contains a ParB/Sulfiredoxin fold with both ATPase and DNase activity, with the DNase activity regulated by ATP[114]. Notably, using a partially reconstituted A. tumefaciens T4SS in vitro, Osa can degrade T-DNA in complex with relaxase before its translocation[115]. Osa from IncW plasmids inhibits conjugation of IncP plasmids by targeting the type IV coupling protein (T4CP), which directs the T-strand: relaxosome complex to the T4SS machinery[114]. In addition to inhibition mediated by Osa, the T4CP seems to be a major checkpoint targeted by FI systems. For instance, FinC, encoded by the mobilizable but non-conjugative plasmid CloDF13, inhibits F plasmid transfer by targeting TraD, the F plasmid T4CP, and this inhibition can be alleviated by traD over-expression[116]. Furthermore, PifC from IncFI or IncI1 plasmids can prevent conjugation of IncW plasmids by T4CP through unknown mechanisms[114].
Conclusions
Less
An arms race between CPs and bacterial defense against parasitism has been raging throughout their evolutionary history. A thorough understanding of this topic is of great clinical importance given the impeding AMR crisis as it potentially allows the prediction of future spread of CPs and can be deployed to devise interventions to combat the emergence of resistance. Although a substantial amount of research on CP-host interactions has been undertaken in the last few decades, many questions remain unanswered, and several challenges lie ahead. Firstly, most studies investigating the molecular mechanisms of CP-host interactions have focused on model plasmids such as the F plasmid in E. coli; studies on more clinically relevant organisms and their CPs, such as K. pneumoniae, A. baumannii, and P. aeruginosa, are needed[117-120]. Moreover, whether “the plasmid paradox” also holds true for clinically relevant AMR-harboring CPs and their bacterial hosts remains unknown and the answer to this question is of great medical importance as this could profoundly influence the outcomes of current measures fighting AMR such as antibiotic stewardship. Those knowledge gaps are largely due to the challenge in genetic manipulation of clinical isolates and require the development of genetic tools for several important pathogens. Another major limitation is that conjugation has mostly been examined in highly artificial environments within the laboratory, while conjugation, as a contact-dependent process, takes place within the dense and heterogeneous bacterial communities in a wide range of environments, particularly in the mammalian gastrointestinal tract. Thus, characterization of conjugation and the factors affecting its efficiency should be performed in more clinically relevant environments such as in the gastrointestinal tract and in biofilms on medical devices[121-123]. Furthermore, the leading region, as discussed above, encodes pro-colonization proteins crucial for thwarting host defense during the early stages of conjugation. However, functions of many genes residing in this region from clinically important CPs remain unstudied and warrant further investigation.
Abbreviations
Less
A. baumannii: Acinetobacter baumannii; A. tumefaciens: Agrobacterium tumefaciens; AMR: Antimicrobial resistance; Cas: CRIPSR-associated; CPs: Conjugative plasmids; E. coli: Escherichia coli; CRISPR: Clustered regularly interspaced palindromic repeats; HGT: Horizontal gene transfer; K. pneumoniae: Klebsiella pneumoniae; MGEs: Mobile genetic elements; MPF: Mating pair formation; MTase: Methyltransferase; NMR: Nuclear magnetic resonance; OB: Oligosaccharide-binding; P. aeruginosa: Pseudomonas aeruginosa; P. putida: Pseudomonas putida; REase: Restriction endonuclease; R-M: Restriction-modification; SMRT: Single-molecule real-time; ssDNA: Single-stranded DNA; SSB: Single-stranded DNA binding; SSB-Ct: C-terminal tail of ssDNA binding proteins; T4CP: Type IV coupling protein; T4SS: Type IV secretion system.
Acknowledgements
Less
We thank Dr. Mariya Lobanovska for her constructive suggestions and comments.
Author contributions
Less
GYL conceptualized the theme of the review. GYL and ZS gathered relevant literature and wrote the manuscript. CMT acquired the funding, wrote and revised the manuscript. All authors read and approved the final manuscript.
Availability of data and materials
Less
Not applicable.
Declarations
Less
Ethics approval and consent to participate
Not applicable.
Consent for publication
Less
Not applicable.
Competing interests
Less
The authors declare that they have no competing interests.
Author details
Less
1Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. 2Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Funding
Less
  • Wellcome Trust, BBSRC, and the National Natural Science Foundation of China(81802065)
  • Wellcome Trust, BBSRC, and the National Natural Science Foundation of China(102908/Z/13/Z)
References
Less
1.
Thomas CM, Nielsen KM. Mechanisms of, and barriers to, horizontal gene transfer between bacteria. Nat Rev Microbiol. 2005;3(9):711-21.
2.
Norman A, Hansen LH, Sørensen SJ. Conjugative plasmids: vessels of the communal gene pool. Philos Trans R Soc Lond B Biol Sci. 2009;364(1527):2275-89.
3.
Partridge SR, Kwong SM, Firth N, Jensen SO. Mobile genetic elements associated with antimicrobial resistance. Clin Microbiol Rev. 2018;31(4):e00088-e117.
4.
Von Wintersdorff CJ, Penders J, Van Niekerk JM, Mills ND, Majumder S, Van Alphen LB, et al. Dissemination of antimicrobial resistance in microbial ecosystems through horizontal gene transfer. Front Microbiol. 2016;7:173.
5.
Soucy SM, Huang J, Gogarten JP. Horizontal gene transfer: building the web of life. Nat Rev Genet. 2015;16(8):472-82.
6.
World Health Organization. The evolving threat of antimicrobial resistance: options for action. World Health Organization, Geneva; 2012.
7.
O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. United Kingdom: Review on Antimicrobial Resistance. 2016.
8.
Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis. 2008;197(8):1079-81.
9.
De Oliveira DMP, Forde BM, Kidd TJ, Harris PNA, Schembri MA, Beatson SA, et al. Antimicrobial resistance in ESKAPE pathogens. Clin Microbiol Rev. 2020;33(3):e00181-219.
10.
Smillie C, Garcillán-Barcia MP, Francia MV, Rocha EPC, De La Cruz F. Mobility of plasmids. Microbiol Mol Biol Rev. 2010;74(3):434-52.
11.
Schröder G, Lanka E. The mating pair formation system of conjugative plasmids-A versatile secretion machinery for transfer of proteins and DNA. Plasmid. 2005;54(1):1-25.
12.
Botelho J, Schulenburg H. The role of integrative and conjugative elements in antibiotic resistance evolution. Trends Microbiol. 2021;29(1):8-18.
13.
Wang R, Van Dorp L, Shaw LP, Bradley P, Wang Q, Wang X, et al. The global distribution and spread of the mobilized colistin resistance gene mcr-1. Nat Commun. 2018;9(1):1179.
14.
Wu W, Feng Y, Tang G, Qiao F, Mcnally A, Zong Z. NDM metallo-β-lactamases and their bacterial producers in health care settings. Clin Microbiol Rev. 2019;32(2):e00115-118.
15.
Yang X, Dong N, Chan EW, Zhang R, Chen S. Carbapenem resistance encoding and virulence-encoding conjugative plasmids in Klebsiella pneumoniae. Trends Microbiol. 2021;29(1):65-83.
16.
Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16(2):161-8.
17.
Quan J, Li X, Chen Y, Jiang Y, Zhou Z, Zhang H, et al. Prevalence of mcr-1 in Escherichia coli and Klebsiella pneumoniae recovered from bloodstream infections in China: a multicentre longitudinal study. Lancet Infect Dis. 2017;17(4):400-10.
18.
Cox KEL, Schildbach JF. Sequence of the R1 plasmid and comparison to F and R100. Plasmid. 2017;91:53-60.
19.
Guglielmini J, Néron B, Abby SS, Garcillán-Barcia MP, De La Cruz F, Rocha EP. Key components of the eight classes of type IV secretion systems involved in bacterial conjugation or protein secretion. Nucleic Acids Res. 2014;42(9):5715-27.
20.
Garcillán-Barcia MP, Francia MV, De La Cruz F. The diversity of conjugative relaxases and its application in plasmid classification. FEMS Microbiol Rev. 2009;33(3):657-87.
21.
Cabezón E, Ripoll-Rozada J, Peña A, De La Cruz F, Arechaga I. Towards an integrated model of bacterial conjugation. FEMS Microbiol Rev. 2015;39(1):81-95.
22.
Virolle C, Goldlust K, Djermoun S, Bigot S, Lesterlin C. Plasmid transfer by conjugation in gram-negative bacteria: from the cellular to the community level. Genes (Basel). 2020;11(11):1239.
23.
Christie PJ. The mosaic type IV secretion systems. EcoSal Plus. 2016;7(1):10.
24.
Grohmann E, Christie PJ, Waksman G, Backert S. Type IV secretion in Gram-negative and Gram-positive bacteria. Mol Microbiol. 2018;107(4):455-71.
25.
Baltrus DA. Exploring the costs of horizontal gene transfer. Trends Ecol Evol. 2013;28(8):489-95.
26.
Koraimann G, Wagner MA. Social behavior and decision making in bacterial conjugation. Front Cell Infect Microbiol. 2014;4:54.
27.
Lu J, Peng Y, Wan S, Frost LS, Raivio T, Glover JNM. Cooperative function of TraJ and ArcA in regulating the F plasmid tra operon. J Bacteriol. 2019;201(1):e00448-518.
28.
Rodriguez-Maillard JM, Arutyunov D, Frost LS. The F plasmid transfer activator TraJ is a dimeric helix-turn-helix DNA-binding protein. FEMS Microbiol Lett. 2010;310(2):112-9.
29.
Mark Glover JN, Chaulk SG, Edwards RA, Arthur D, Lu J, Frost LS. The FinO family of bacterial RNA chaperones. Plasmid. 2015;78:79-87.
30.
Frost L, Lee S, Yanchar N, Paranchych W. finP and fisO mutations in FinP anti-sense RNA suggest a model for FinOP action in the repression of bacterial conjugation by the Flac plasmid JCFL0. Mol Gen Genet. 1989;218(1):152-60.
31.
Koraimann G, Teferle K, Markolin G, Woger W, Högenauer G. The FinOP repressor system of plasmid R1 analysis of the antisense RNA control of traJ expression and conjugative DNA transfer. Mol Microbiol. 1996;21(4):811-21.
32.
van Biesen T, Frost LS. The FinO protein of IncF plasmids binds FinP antisense RNA and its target, traJ mRNA, and promotes duplex formation. Mol Microbiol. 1994;14(3):427-36.
33.
Arthur DC, Edwards RA, Tsutakawa S, Tainer JA, Frost LS, Glover JN. Mapping interactions between the RNA chaperone FinO and its RNA targets. Nucleic Acids Res. 2011;39(10):4450-63.
34.
Zahrl D, Wagner M, Bischof K, Koraimann G. Expression and assembly of a functional type IV secretion system elicit extracytoplasmic and cytoplasmic stress responses in Escherichia coli. J Bacteriol. 2006;188(18):6611-21.
35.
Bidlack JE, Silverman PM. An active type IV secretion system encoded by the F plasmid sensitizes Escherichia coli to bile salts. J Bacteriol. 2004;186(16):5202-9.
36.
Grace ED, Gopalkrishnan S, Girard ME, Blankschien MD, Ross W, Gourse RL, et al. Activation of the σE-dependent stress pathway by conjugative TraR may anticipate conjugational stress. J Bacteriol. 2015;197(5):924-31.
37.
Bates S, Roscoe RA, Althorpe NJ, Brammar WJ, Wilkins BM. Expression of leading region genes on IncI1 plasmid ColIb-P9: genetic evidence for single-stranded DNA transcription. Microbiology (Reading). 1999;145(Pt 10):2655-62.
38.
Manwaring NP, Skurray RA, Firth N. Nucleotide sequence of the F plasmid leading region. Plasmid. 1999;41(3):219-25.
39.
Jones AL, Barth PT, Wilkins BM. Zygotic induction of plasmid ssb and psiB genes following conjugative transfer of Incl1 plasmid Collb-P9. Mol Microbiol. 1992;6(5):605-13.
40.
Masai H, Arai K. Frpo: a novel single-stranded DNA promoter for transcription and for primer RNA synthesis of DNA replication. Cell. 1997;89(6):897-907.
41.
Althorpe NJ, Chilley PM, Thomas AT, Brammar WJ, Wilkins BM. Transient transcriptional activation of the IncI1 plasmid anti-restriction gene (ardA) and SOS inhibition gene (psiB) early in conjugating recipient bacteria. Mol Microbiol. 1999;31(1):133-42.
42.
Raghunathan S, Kozlov AG, Lohman TM, Waksman G. Structure of the DNA binding domain of E. coli SSB bound to ssDNA. Nat Struct Biol. 2000;7(8):648-52.
43.
Savvides SN, Raghunathan S, Fütterer K, Kozlov AG, Lohman TM, Waksman G. The C-terminal domain of full-length E. coli SSB is disordered even when bound to DNA. Protein Sci. 2004;13(7):1942-7.
44.
Shamoo Y, Friedman AM, Parsons MR, Konigsberg WH, Steitz TA. Crystal structure of a replication fork single-stranded DNA binding protein (T4 gp32) complexed to DNA. Nature. 1995;376(6538):362-6.
45.
Bianco PR. The tale of SSB. Prog Biophys Mol Biol. 2017;127:111-8.
46.
Zhou R, Kozlov AG, Roy R, Zhang J, Korolev S, Lohman TM, et al. SSB functions as a sliding platform that migrates on DNA via reptation. Cell. 2011;146(2):222-32.
47.
Harami GM, Kovacs ZJ, Pancsa R, Palinkas J, Barath V, Tarnok K, et al. Phase separation by ssDNA binding protein controlled via proteinprotein and protein-DNA interactions. Proc Natl Acad Sci U S A. 2020;117(42):26206-17.
48.
Costes A, Lecointe F, Mcgovern S, Quevillon-Cheruel S, Polard P. The C-terminal domain of the bacterial SSB protein acts as a DNA maintenance hub at active chromosome replication forks. PLoS Genet. 2010;6(12):e1001238.
49.
Marceau AH, Bahng S, Massoni SC, George NP, Sandler SJ, Marians KJ, et al. Structure of the SSB-DNA polymerase III interface and its role in DNA replication. EMBO J. 2011;30(20):4236-47.
50.
Roy R, Kozlov AG, Lohman TM, Ha T. SSB protein diffusion on single-stranded DNA stimulates RecA filament formation. Nature. 2009;461(7267):1092-7.
51.
Shinn MK, Kozlov AG, Lohman TM. Allosteric effects of SSB C-terminal tail on assembly of E. coli RecOR proteins. Nucleic Acids Res. 2021;49(4):1987-2004.
52.
Nolivos S, Cayron J, Dedieu A, Page A, Delolme F, Lesterlin C. Role of AcrAB-TolC multidrug efflux pump in drug-resistance acquisition by plasmid transfer. Science. 2019;364(6442):778-82.
53.
Roy D, Huguet KT, Grenier F, Burrus V. IncC conjugative plasmids and SXT/R391 elements repair double-strand breaks caused by CRISPR-Cas during conjugation. Nucleic Acids Res. 2020;48(16):8815-27.
54.
Baharoglu Z, Bikard D, Mazel D. Conjugative DNA transfer induces the bacterial SOS response and promotes antibiotic resistance development through integron activation. PLoS Genet. 2010;6(10):e1001165.
55.
Maslowska KH, Makiela-Dzbenska K, Fijalkowska IJ. The SOS system: a complex and tightly regulated response to DNA damage. Environ Mol Mutagen. 2019;60(4):368-84.
56.
Michel B. After 30 years of study, the bacterial SOS response still surprises us. PLoS Biol. 2005;3(7):e255.
57.
Baharoglu Z, Mazel D. SOS, the formidable strategy of bacteria against aggressions. FEMS Microbiol Rev. 2014;38(6):1126-45.
58.
Murata M, Nakamura K, Kosaka T, Ota N, Osawa A, Muro R, et al. Cell Lysis Directed by SulA in Response to DNA Damage in Escherichia coli. Int J Mol Sci. 2021;22(9).
59.
Petrova V, Satyshur KA, George NP, Mccaslin D, Cox MM, Keck JL. X-ray crystal structure of the bacterial conjugation factor PsiB, a negative regulator of RecA. J Biol Chem. 2010;285(40):30615-21.
60.
Bagdasarian M, Bailone A, Angulo JF, Scholz P, Bagdasarian M, Devoret R. PsiB, and anti-SOS protein, is transiently expressed by the F sex factor during its transmission to an Escherichia coli K-12 recipient. Mol Microbiol. 1992;6(7):885-93.
61.
Al Mamun AAM, Kishida K, Christie PJ. Protein transfer through an F plasmid-encoded type IV secretion system suppresses the matinginduced SOS response. mBio. 2021;12(4):e01629-21.
62.
Petrova V, Chitteni-Pattu S, Drees JC, Inman RB, Cox MM. An SOS inhibitor that binds to free RecA protein: the PsiB protein. Mol Cell. 2009;36(1):121-30.
63.
Loenen WA, Dryden DT, Raleigh EA, Wilson GG. Type I restriction enzymes and their relatives. Nucleic Acids Res. 2014;42(1):20-44.
64.
Loenen WA, Dryden DT, Raleigh EA, Wilson GG, Murray NE. Highlights of the DNA cutters: a short history of the restriction enzymes. Nucleic Acids Res. 2014;42(1):3-19.
65.
Rao DN, Dryden DT, Bheemanaik S. Type III restriction-modification enzymes: a historical perspective. Nucleic Acids Res. 2014;42(1):45-55.
66.
Tock MR, Dryden DT. The biology of restriction and anti-restriction. Curr Opin Microbiol. 2005;8(4):466-72.
67.
Wilkins BM. Plasmid promiscuity: meeting the challenge of DNA immigration control. Environ Microbiol. 2002;4(9):495-500.
68.
Delver EP, Kotova VU, Zavilgelsky GB, Belogurov AA. Nucleotide sequence of the gene (ard) encoding the antirestriction protein of plasmid ColIb-P9. J Bacteriol. 1991;173(18):5887-92.
69.
Nekrasov SV, Agafonova OV, Belogurova NG, Delver EP, Belogurov AA. Plasmid-encoded antirestriction protein ArdA can discriminate between type I methyltransferase and complete restriction-modification system. J Mol Biol. 2007;365(2):284-97.
70.
Mcmahon SA, Roberts GA, Johnson KA, Cooper LP, Liu H, White JH, et al. Extensive DNA mimicry by the ArdA anti-restriction protein and its role in the spread of antibiotic resistance. Nucleic Acids Res. 2009;37(15):4887-97.
71.
Gao Y, Cao D, Zhu J, Feng H, Luo X, Liu S, et al. Structural insights into assembly, operation and inhibition of a type I restriction-modification system. Nat Microbiol. 2020;5(9):1107-18.
72.
Belogurov AA, Delver EP, Rodzevich OV. Plasmid pKM101 encodes two nonhomologous antirestriction proteins (ArdA and ArdB) whose expression is controlled by homologous regulatory sequences. J Bacteriol. 1993;175(15):4843-50.
73.
Serfiotis-Mitsa D, Herbert AP, Roberts GA, Soares DC, White JH, Blakely GW, et al. The structure of the KlcA and ArdB proteins reveals a novel fold and antirestriction activity against type I DNA restriction systems in vivo but not in vitro. Nucleic Acids Res. 2010;38(5):1723-37.
74.
Kamachi K, Sota M, Tamai Y, Nagata N, Konda T, Inoue T, et al. Plasmid pBP136 from Bordetella pertussis represents an ancestral form of IncP-1beta plasmids without accessory mobile elements. Microbiology (Reading). 2006;152(Pt 12):3477-84.
75.
Liang W, Xie Y, Xiong W, Tang Y, Li G, Jiang X, et al. Anti-restriction protein, KlcAHS, promotes dissemination of carbapenem resistance. Front Cell Infect Microbiol. 2017;7:150.
76.
Liang W, Tang Y, Li G, Shen P, Tian Y, Jiang H, et al. KlcAHS genes are ubiquitous in clinical, blaKPC-2-positive Klebsiella pneumoniae isolates. Infect Genet Evol. 2019;70:84-9.
77.
Belogurov AA, Delver EP, Agafonova OV, Belogurova NG, Lee LY, Kado CI. Antirestriction protein Ard (Type C) encoded by IncW plasmid pSa has a high similarity to the “protein transport” domain of TraC1 primase of promiscuous plasmid RP4. J Mol Biol. 2000;296(4):969-77.
78.
González-Montes L, Del Campo I, Garcillán-Barcia MP, De La Cruz F, Moncalian G. ArdC, a ssDNA-binding protein with a metalloprotease domain, overpasses the recipient hsdRMS restriction system broadening conjugation host range. PLoS Genet. 2020;16(4):e1008750.
79.
Rees CE, Wilkins BM. Protein transfer into the recipient cell during bacterial conjugation studies with F and RP4. Mol Microbiol. 1990;4(7):1199-205.
80.
Marinus MG, Casadesus J. Roles of DNA adenine methylation in hostpathogen interactions: mismatch repair, transcriptional regulation, and more. FEMS Microbiol Rev. 2009;33(3):488-503.
81.
Blow MJ, Clark TA, Daum CG, Deutschbauer AM, Fomenkov A, Fries R, et al. The epigenomic landscape of prokaryotes. PLoS Genet. 2016;12(2):e1005854.
82.
Fang G, Munera D, Friedman DI, Mandlik A, Chao MC, Banerjee O, et al. Genome-wide mapping of methylated adenine residues in pathogenic Escherichia coli using single-molecule real-time sequencing. Nat Biotechnol. 2012;30(12):1232-9.
83.
Yamaichi Y, Chao MC, Sasabe J, Clark L, Davis BM, Yamamoto N, et al. High-resolution genetic analysis of the requirements for horizontal transmission of the ESBL plasmid from Escherichia coli O104:H4. Nucleic Acids Res. 2015;43(1):348-60.
84.
Sampei GI, Furuya N, Tachibana K, Saitou Y, Suzuki T, Mizobuchi K, et al. Complete genome sequence of the incompatibility group I1 plasmid R64. Plasmid. 2010;64(2):92-103.
85.
Holden MT, Seth-Smith HM, Crossman LC, Sebaihia M, Bentley SD, Cerdeno-Tarraga AM, et al. The genome of Burkholderia cenocepacia J2315, an epidemic pathogen of cystic fibrosis patients. J Bacteriol. 2009;191(1):261-77.
86.
Fomenkov A, Sun Z, Murray IA, Ruse C, Mcclung C, Yamaichi Y, et al. Plasmid replication-associated single-strand-specific methyltransferases. Nucleic Acids Res. 2020;48(22):12858-73.
87.
Smith J. Superinfection drives virulence evolution in experimental populations of bacteria and plasmids. Evolution. 2011;65(3):831-41.
88.
Subbiah M, Top EM, Shah DH, Call DR. Selection pressure required for long-term persistence of blaCMY-2-positive IncA/C plasmids. Appl Environ Microbiol. 2011;77(13):4486-93.
89.
Harrison E, Brockhurst MA. Plasmid-mediated horizontal gene transfer is a coevolutionary process. Trends Microbiol. 2012;20(6):262-7.
90.
Carroll AC, Wong A. Plasmid persistence: costs, benefits, and the plasmid paradox. Can J Microbiol. 2018;64(5):293-304.
91.
Brockhurst MA, Harrison E. Ecological and evolutionary solutions to the plasmid paradox. Trends Microbiol. 2021. https://doi.org/10.1016/j.tim.2021.11.001.
92.
Salje J, Gayathri P, Löwe J. The ParMRC system: molecular mechanisms of plasmid segregation by actin-like filaments. Nat Rev Microbiol. 2010;8(10):683-92.
93.
Pilla G, Tang CM. Going around in circles: virulence plasmids in enteric pathogens. Nat Rev Microbiol. 2018;16(8):484-95.
94.
Gerdes K, Howard M, Szardenings F. Pushing and pulling in prokaryotic DNA segregation. Cell. 2010;141(6):927-42.
95.
Harms A, Brodersen DE, Mitarai N, Gerdes K. Toxins, targets, and triggers: an overview of toxin-antitoxin biology. Mol Cell. 2018;70(5):768-84.
96.
Schumacher MA. Bacterial plasmid partition machinery: a minimalist approach to survival. Curr Opin Struct Biol. 2012;22(1):72-9.
97.
Garcillán-Barcia MP, de la Cruz F. Why is entry exclusion an essential feature of conjugative plasmids? Plasmid. 2008;60(1):1-18.
98.
Humbert M, Huguet KT, Coulombe F, Burrus V. Entry exclusion of conjugative plasmids of the IncA, IncC, and related untyped incompatibility groups. J Bacteriol. 2019;201(10):e00731-818.
99.
Frost LS, Ippen-Ihler K, Skurray RA. Analysis of the sequence and gene products of the transfer region of the F sex factor. Microbiol Rev. 1994;58(2):162-210.
100.
Achtman M, Kennedy N, Skurray R. Cell-cell interactions in conjugating Escherichia coli: role of traT protein in surface exclusion. Proc Natl Acad Sci U S A. 1977;74(11):5104-8.
101.
Firth N, Skurray R. Characterization of the F plasmid bifunctional conjugation gene, traG. Mol Gen Genet. 1992;232(1):145-53.
102.
Audette GF, Manchak J, Beatty P, Klimke WA, Frost LS. Entry exclusion in F-like plasmids requires intact TraG in the donor that recognizes its cognate TraS in the recipient. Microbiology (Reading). 2007;153(Pt 2):442-51.
103.
Achtman M, Manning PA, Kusecek B, Schwuchow S, Neil W. A genetic analysis of F sex factor cistrons needed for surface exclusion in Escherichia coli. J Mol Biol. 1980;138(4):779-95.
104.
Skurray RA, Reeves P. Characterization of lethal zygosis associated with conjugation in Escherichia coli K-12. J Bacteriol. 1973;113(1):58-70.
105.
Bertozzi Silva J, Storms Z, Sauvageau D. Host receptors for bacteriophage adsorption. FEMS Microbiol Lett. 2016;363(4):fnw002.
106.
Getino M, de la Cruz F. Natural and artificial strategies to control the conjugative transmission of plasmids. Microbiol Spectr. 2018. https://doi.org/10.1128/microbiolspec.MTBP-0015-2016.
107.
Dionisio F, Zilhão R, Gama JA. Interactions between plasmids and other mobile genetic elements affect their transmission and persistence. Plasmid. 2019;102:29-36.
108.
Gama JA, Zilhão R, Dionisio F. Impact of plasmid interactions with the chromosome and other plasmids on the spread of antibiotic resistance. Plasmid. 2018;99:82-8.
109.
Gasson MJ, Willetts NS. Five control systems preventing transfer of Escherichia coli K-12 sex factor F. J Bacteriol. 1975;122(2):518-25.
110.
Wong JJW, Lu J, Edwards RA, Frost LS, Glover JNM. Structural basis of cooperative DNA recognition by the plasmid conjugation factor. TraM Nucleic Acids Res. 2011;39(15):6775-88.
111.
Peng Y, Lu J, Wong JJW, Edwards RA, Frost LS, Mark Glover JN. Mechanistic basis of plasmid-specific DNA binding of the F plasmid regulatory protein. TraM J Mol Biol. 2014;426(22):3783-95.
112.
Ham LM, Skurray R. Molecular analysis and nucleotide sequence of finQ, a transcriptional inhibitor of the F plasmid transfer genes. Mol Gen Genet. 1989;216(1):99-105.
113.
Close SM, Kado CI. The Osa gene of pSa encodes a 211-kilodalton protein that suppresses Agrobacterium tumefaciens oncogenicity. J Bacteriol. 1991;173(17):5449-56.
114.
Getino M, Palencia-Gándara C, Garcillán-Barcia MP, De La Cruz F. PifC and Osa, plasmid weapons against rival conjugative coupling proteins. Front Microbiol. 2017;8:2260.
115.
Maindola P, Raina R, Goyal P, Atmakuri K, Ojha A, Gupta S, et al. Multiple enzymatic activities of ParB/Srx superfamily mediate sexual conflict among conjugative plasmids. Nat Commun. 2014;5:5322.
116.
Willetts N. Interactions between the F conjugal transfer system and CloDF13: TnA plasmids. Mol Gen Genet. 1980;180(1):213-7.
117.
Zhong L, Shi XZ, Su L, Liu ZF. Sequential intraventricular injection of tigecycline and polymyxin B in the treatment of intracranial Acinetobacter baumannii infection after trauma: a case report and review of the literature. Mil Med Res. 2020;7(1):23.
118.
Botelho J, Grosso F, Peixe L. Antibiotic resistance in Pseudomonas aeruginosa-Mechanisms, epidemiology and evolution. Drug Resist Updat. 2019;44:100640.
119.
Navon-Venezia S, Kondratyeva K, Carattoli A. Klebsiella pneumoniae: a major worldwide source and shuttle for antibiotic resistance. FEMS Microbiol Rev. 2017;41(3):252-75.
120.
Asif M, Alvi IA, Rehman SU. Insight into Acinetobacter baumannii: pathogenesis, global resistance, mechanisms of resistance, treatment options, and alternative modalities. Infect Drug Resist. 2018;11:1249-60.
121.
Stalder T, Top E. Plasmid transfer in biofilms: a perspective on limitations and opportunities. NPJ Biofilms Microbiomes. 2016;2:16022.
122.
Li C, Chen J, Li SC. Understanding Horizontal Gene Transfer network in human gut microbiota. Gut Pathog. 2020;12:33.
123.
Shi N, Li N, Duan X, Niu H. Interaction between the gut microbiome and mucosal immune system. Mil Med Res. 2017;4:14.
Appendix
Less
Year 2022 volume 9 Issue 5
PDF
54
30
Cite this Article
BibTeX
Article Info
doi: 10.1186/s40779-021-00362-z
  • Online Date：2025-12-22
  • Published：2022-10-10
Article Data
Affiliations
History
Funding
Wellcome Trust, BBSRC, and the National Natural Science Foundation of China(81802065)
Wellcome Trust, BBSRC, and the National Natural Science Foundation of China(102908/Z/13/Z)
Affiliations
    1Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
    2Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China

Corresponding:

References
Share
https://castjournals.cast.org.cn/joweb/mmr/EN/10.1186/s40779-021-00362-z
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
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
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House