微生物学报

Access method of ARGs	Species	ARGs	Resistance mechanism	Characteristics	Fitness cost	Reference
Genetic mutation	Staphylococcus epidermidis	rpoB	Prevent the interaction between rifampicin and the β-subunit of RNA polymerase	The growth rate decreases	RF: <1.0	[27]
Pseudomonas aeruginosa	nfxB	Regulators of multidrug efflux pumps	A large amount of energy is consumed, and the growth rate decreases	Growth curves:P<0.000 1	[28]
gyrA, gyrB	Prevent fluoroquinolones from binding to DNA-modifying subunits of DNA gyrases	No fitness cost	RF: 1.012 (gyrA),1.003 (gyrB)
Mycolicibacterium smegmatis	rv2752c	Encoding a bifunctional RNase J protein with β-lactamase and ribonuclease activities	Decreased transcription efficiency and reduced growth rate	RF: 0.87	[29]
Conjugation	Escherichia coli	bla_CTX-M-14	Enzymes that hydrolyze penicillin and third-generation cephalosporins	Some bacteria lose their conjugative ability	RF: 0.985	[30]
bla_NDM	Enzymes that hydrolyze carbapenem drugs	Decreased virulence and loss of plasmids	RF: 0.813 006	[31]
qnrA, qnrB, qnrS	Protect DNA gyrase and topoisomerase IV from inhibition by quinolone drugs	No fitness cost	RF: 1.030 (qnrA), 1.056 (qnrB), 1.016 (qnrS)	[32]
Salmonella	fosA7	Produce fosfomycin-modifying enzymes	The growth rate is not affected	Growth curves:P=0.844 1	[33]
Transposon	Escherichia coli	sul1,sul2,sul3	Dihydropteroate synthase with low affinity for sulfonamide drugs	The motility is decreased, and the growth rate is reduced (sul3)	S: 0.021>0 (sul1), 0.019>0 (sul2), -0.087<0 (sul3)	[34]
Enterococcus faecium	vanA	The encoded protein alters the synthesis of cell wall peptidoglycan precursors	The growth rate decreases	Growth curves:P<0.001	[35]
Integrator	Escherichia coli	dfrA1-sat2-aadA1	Type II integrons carry gene cassettes with a multi-resistance pattern	The growth rate decreases	S: -0.068<0	[36]
Transduction	Streptococcus suis	mef(A), tet(O)	Efflux pump proteins and ribosome protection proteins	The growth rate increases	Growth curves: the logarithmic phase (2 hours earlier) and the OD₆₉₀peak (3 hours earlier and being 0.25 higher)	[37]
Escherichia coli	bla_CTX-M-55	Enzymes for multiple β-lactam drugs	The growth rate and elevated plasmid loss rate increases (P1)	RF: <1 (No P1), >1 (P1)	[38]

Access method of ARGs	Species	ARGs	Resistance mechanism	Characteristics	Fitness cost	Reference
Genetic mutation	Staphylococcus epidermidis	rpoB	Prevent the interaction between rifampicin and the β-subunit of RNA polymerase	The growth rate decreases	RF: <1.0	[27]
Pseudomonas aeruginosa	nfxB	Regulators of multidrug efflux pumps	A large amount of energy is consumed, and the growth rate decreases	Growth curves:P<0.000 1	[28]
gyrA, gyrB	Prevent fluoroquinolones from binding to DNA-modifying subunits of DNA gyrases	No fitness cost	RF: 1.012 (gyrA),1.003 (gyrB)
Mycolicibacterium smegmatis	rv2752c	Encoding a bifunctional RNase J protein with β-lactamase and ribonuclease activities	Decreased transcription efficiency and reduced growth rate	RF: 0.87	[29]
Conjugation	Escherichia coli	bla_CTX-M-14	Enzymes that hydrolyze penicillin and third-generation cephalosporins	Some bacteria lose their conjugative ability	RF: 0.985	[30]
bla_NDM	Enzymes that hydrolyze carbapenem drugs	Decreased virulence and loss of plasmids	RF: 0.813 006	[31]
qnrA, qnrB, qnrS	Protect DNA gyrase and topoisomerase IV from inhibition by quinolone drugs	No fitness cost	RF: 1.030 (qnrA), 1.056 (qnrB), 1.016 (qnrS)	[32]
Salmonella	fosA7	Produce fosfomycin-modifying enzymes	The growth rate is not affected	Growth curves:P=0.844 1	[33]
Transposon	Escherichia coli	sul1,sul2,sul3	Dihydropteroate synthase with low affinity for sulfonamide drugs	The motility is decreased, and the growth rate is reduced (sul3)	S: 0.021>0 (sul1), 0.019>0 (sul2), -0.087<0 (sul3)	[34]
Enterococcus faecium	vanA	The encoded protein alters the synthesis of cell wall peptidoglycan precursors	The growth rate decreases	Growth curves:P<0.001	[35]
Integrator	Escherichia coli	dfrA1-sat2-aadA1	Type II integrons carry gene cassettes with a multi-resistance pattern	The growth rate decreases	S: -0.068<0	[36]
Transduction	Streptococcus suis	mef(A), tet(O)	Efflux pump proteins and ribosome protection proteins	The growth rate increases	Growth curves: the logarithmic phase (2 hours earlier) and the OD₆₉₀peak (3 hours earlier and being 0.25 higher)	[37]
Escherichia coli	bla_CTX-M-55	Enzymes for multiple β-lactam drugs	The growth rate and elevated plasmid loss rate increases (P1)	RF: <1 (No P1), >1 (P1)	[38]

Vector	Mechanism	Drug	ARGs	Impacted cost pathway	Fitness cost	Reference
Chromosome	Reduced permeability	The extended-spectrum	ompC/F	Impaired nutrient absorption→DNA methylation→DNA binding to proteins	Arrested the growth and replication of bacteria	[40-41]
ompC/F	Decreased expression of csgA/B→impaired curli synthesis	Decreased biofilm formation	[42-43]
Active transport of antibiotics	The extended-spectrum	—	Overexpression of efflux pumps	High energy burden	[15]
mexABOprM, mexCDOprJ	Impact on the rhl QS system→reduced phenazine synthesis; lack of MexA	Decreased virulence	[44]
mexEFOprN	Pumping out PQS precursors→delayed production of PQS signaling molecules	Impaired initiation of PQS function, decreased virulence	[45]
mexEFOprN	H⁺antiport→intracellular H⁺ accumulation	Imbalance of pH homeostasis	[46]
ade group	Downregulated expression of pili and membrane structural proteins	Decreased biofilm formation	[47]
acrABTolC	Promotion of QS signal AHL efflux→binding to membrane receptor SdiA	Promotion of biofilm formation	[48]
Target modification	Aminoglycosides	rrs	A1408G mutation in 16S rRNA gene→no impact on the ON/OFF switching of the A site	No fitness cost	[49]
rrs	A1408C/U mutations in 16S rRNA gene→affect the ON/OFF switching of the A site	Bacterial death	[49]
Rifampicin	ropB	Alteration of the conserved β subunit of RNA polymerase	Decreased transcription efficiency	[6,50]
Plasmid	Inactivation and modification of the drug	β-lactams	bla_KPC-2	Downregulated expression of virulence genes iucA, magA, and rmpA2	Decreased virulence	[51]
bla_FOX-4/8	Overexpression of AmpC enzyme→abnormal peptidoglycan metabolism→interference with cell wall integrity	Decreased virulence	[52]
bla_NDM	Downregulation of locomotion, ATP synthesis, and DNA replication	Decreased motility and replicative capacity	[11]
Tetracyclines	tet(X4)	Downregulated expression of atlR→inability to inhibit the copy number of plasmids	Decreased biofilm formation and virulence	[53]
tetX	Increased ATPase activity and protein synthesis	Increased metabolic burden	[54]
tet(X4)	Encoded the H-NS protein→inhibits tet(X4) expression	No fitness cost	[55]
Active transport of antibiotics	Tetracyclines	tetH	Downregulated expression of fimbrial genes fimA and fimC	Decreased motility	[56]
tetA	Decreased K⁺ uptake efficiency of the Trk system	High energy consumption	[57]
Quinolones	qepA2,oqxAB	gyrA/B mutations that induce the target modification mechanism	Enhanced fitness	[58-59]
Target modification	Glycopeptides	van	Modification of peptidoglycan→defect in sporulation	Decreased infectivity	[60]
Aminoglycosides	armA	Resistant methylation of A1405 in 16S rRNA gene	No fitness cost	[61]
armA	Interference with the endogenous methylation of C1402 by RsmI	Affects ribosome function	[61]
npmA	Resistant methylation of A1408 in 16S rRNA gene	No fitness cost	[61]
npmA	Block the activity of RsmF on C1407	Reduces the accuracy of translation	[61]
Macrolides	cfr	Expression of cfr→resistant methylation of A2503 in 16S rRNA gene	No fitness cost	[62]
cfr	Co-expression of ermB and cfr→dimethylation of A2508	Obstruction of the export tunnel for nascent peptide synthesis	[62]
Polymyxins	mcr-1	Modification of lipid A→obstruction of LPS synthesis	Decreased virulence	[63]
mcr-1	Modification of LPS→downregulation of waa and rml→downregulation of LPS core and O-antigen synthesis	Increased membrane permeability and membrane depolarization	[64]

Vector	Mechanism	Drug	ARGs	Impacted cost pathway	Fitness cost	Reference
Chromosome	Reduced permeability	The extended-spectrum	ompC/F	Impaired nutrient absorption→DNA methylation→DNA binding to proteins	Arrested the growth and replication of bacteria	[40-41]
ompC/F	Decreased expression of csgA/B→impaired curli synthesis	Decreased biofilm formation	[42-43]
Active transport of antibiotics	The extended-spectrum	—	Overexpression of efflux pumps	High energy burden	[15]
mexABOprM, mexCDOprJ	Impact on the rhl QS system→reduced phenazine synthesis; lack of MexA	Decreased virulence	[44]
mexEFOprN	Pumping out PQS precursors→delayed production of PQS signaling molecules	Impaired initiation of PQS function, decreased virulence	[45]
mexEFOprN	H⁺antiport→intracellular H⁺ accumulation	Imbalance of pH homeostasis	[46]
ade group	Downregulated expression of pili and membrane structural proteins	Decreased biofilm formation	[47]
acrABTolC	Promotion of QS signal AHL efflux→binding to membrane receptor SdiA	Promotion of biofilm formation	[48]
Target modification	Aminoglycosides	rrs	A1408G mutation in 16S rRNA gene→no impact on the ON/OFF switching of the A site	No fitness cost	[49]
rrs	A1408C/U mutations in 16S rRNA gene→affect the ON/OFF switching of the A site	Bacterial death	[49]
Rifampicin	ropB	Alteration of the conserved β subunit of RNA polymerase	Decreased transcription efficiency	[6,50]
Plasmid	Inactivation and modification of the drug	β-lactams	bla_KPC-2	Downregulated expression of virulence genes iucA, magA, and rmpA2	Decreased virulence	[51]
bla_FOX-4/8	Overexpression of AmpC enzyme→abnormal peptidoglycan metabolism→interference with cell wall integrity	Decreased virulence	[52]
bla_NDM	Downregulation of locomotion, ATP synthesis, and DNA replication	Decreased motility and replicative capacity	[11]
Tetracyclines	tet(X4)	Downregulated expression of atlR→inability to inhibit the copy number of plasmids	Decreased biofilm formation and virulence	[53]
tetX	Increased ATPase activity and protein synthesis	Increased metabolic burden	[54]
tet(X4)	Encoded the H-NS protein→inhibits tet(X4) expression	No fitness cost	[55]
Active transport of antibiotics	Tetracyclines	tetH	Downregulated expression of fimbrial genes fimA and fimC	Decreased motility	[56]
tetA	Decreased K⁺ uptake efficiency of the Trk system	High energy consumption	[57]
Quinolones	qepA2,oqxAB	gyrA/B mutations that induce the target modification mechanism	Enhanced fitness	[58-59]
Target modification	Glycopeptides	van	Modification of peptidoglycan→defect in sporulation	Decreased infectivity	[60]
Aminoglycosides	armA	Resistant methylation of A1405 in 16S rRNA gene	No fitness cost	[61]
armA	Interference with the endogenous methylation of C1402 by RsmI	Affects ribosome function	[61]
npmA	Resistant methylation of A1408 in 16S rRNA gene	No fitness cost	[61]
npmA	Block the activity of RsmF on C1407	Reduces the accuracy of translation	[61]
Macrolides	cfr	Expression of cfr→resistant methylation of A2503 in 16S rRNA gene	No fitness cost	[62]
cfr	Co-expression of ermB and cfr→dimethylation of A2508	Obstruction of the export tunnel for nascent peptide synthesis	[62]
Polymyxins	mcr-1	Modification of lipid A→obstruction of LPS synthesis	Decreased virulence	[63]
mcr-1	Modification of LPS→downregulation of waa and rml→downregulation of LPS core and O-antigen synthesis	Increased membrane permeability and membrane depolarization	[64]

抗生素抗性菌的适应性代价及其防控策略研究进展

PDF下载

罗裔宵 ¹ , 陈洁蓉 ¹ , 罗智聪 ¹ , 郑昕晨 ¹ , 罗俊金 ¹ , 黎玥 ¹ , 温馨 ¹ , 陈涛 ² , 吴银宝 ¹^,³^,⁴

微生物学报 | 综述 2026,66(2): 595-609

收起

微生物学报 | 综述 2026, 66(2): 595-609

抗生素抗性菌的适应性代价及其防控策略研究进展

全屏

罗裔宵¹, 陈洁蓉¹, 罗智聪¹, 郑昕晨¹, 罗俊金¹, 黎玥¹, 温馨¹, 陈涛², 吴银宝¹^,³^,⁴

作者信息

^1.华南农业大学动物科学学院，广东广州

^2.山东农业大学动物科技学院，山东泰安

^3.猪禽种业全国重点实验室，广东广州

^4.广东省农业动物基因组学与分子育种重点实验室，广东广州

Research progress in the fitness cost and prevention and control strategies of antibiotic resistant bacteria

Yixiao LUO¹, Jierong CHEN¹, Zhicong LUO¹, Xinchen ZHENG¹, Junjin LUO¹, Yue LI¹, Xin WEN¹, Tao CHEN², Yinbao WU¹^,³^,⁴

Affiliations

^1.College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China

^2.College of Animal Science and Technology, Shandong Agricultural University, Tai’an, Shandong, China

^3.State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou, Guangdong, China

^4.Guangdong Provincial Key Lab of Agro-animal Genomics and Molecular Breeding, Guangzhou, Guangdong, China

出版时间: 2026-02-04 doi: 10.13343/j.cnki.wsxb.20250668

文章导航

摘要

收起

微生物的抗生素抗性(antibiotic resistance, AR)问题已成为全球公共卫生安全面临的重大挑战。微生物获得AR后常伴随适应性代价，通常在无抗生素环境中其群落竞争力弱于敏感菌，这使得抗生素抗性基因(antibiotic resistance genes, ARGs)成为细菌的负担。基于此，本文详细阐述了适应性代价的产生机制与测量方法，举例说明了不同获取方式下ARGs介导的适应性代价，着重介绍了染色体介导和质粒介导的ARGs在适应性代价方面的差异及分子机制，最后提出了基于适应性代价的抗生素抗性菌(antibiotic resistance bacteria, ARB)防控策略。本文揭示了抗生素抗性与细菌适应性之间的权衡生物学规律，为解决由ARB及ARGs引发的全球公共卫生安全问题提供了防控思路。

关键词

抗生素抗性菌 / 适应性代价 / 抗性机制 / 水平基因转移 / 防控

Abstract

收起

Antibiotic resistance (AR) in microorganisms has become a crucial challenge to global public health security. The acquirement of AR in microorganisms is often accompanied by a fitness cost. Typically, in an environment without antibiotics, the bacterial community with AR shows weaker competitiveness than susceptible bacteria, which makes antibiotic resistance genes (ARGs) a burden for bacteria. This article elaborates on the mechanisms underlying the generation of fitness costs and the corresponding measurement methods, provides examples to illustrate the fitness costs mediated by ARGs under different acquisition methods, and introduces the differences in fitness costs between chromosome-mediated and plasmid-mediated ARGs as well as their molecular mechanisms. Finally, it proposes prevention and control strategies for antibiotic resistant bacteria (ARB) based on fitness costs. This article reveals the biological law of the trade-off between antibiotic resistance and bacterial fitness and provides ideas for preventing and controlling the global public health security issues caused by ARB and ARGs.

Key words

antibiotic resistant bacteria / fitness cost / resistance mechanism / horizontal gene transfer / prevention and control

引用本文

罗裔宵, 陈洁蓉, 罗智聪, 郑昕晨, 罗俊金, 黎玥, 温馨, 陈涛, 吴银宝. 抗生素抗性菌的适应性代价及其防控策略研究进展. 微生物学报, 2026 , 66 (2) : 595 -609 . DOI: 10.13343/j.cnki.wsxb.20250668

Yixiao LUO, Jierong CHEN, Zhicong LUO, Xinchen ZHENG, Junjin LUO, Yue LI, Xin WEN, Tao CHEN, Yinbao WU. Research progress in the fitness cost and prevention and control strategies of antibiotic resistant bacteria[J]. Acta Microbiologica Sinica, 2026 , 66 (2) : 595 -609 . DOI: 10.13343/j.cnki.wsxb.20250668

正文

收起

抗生素在养殖业和人类临床的大量使用导致抗生素抗性基因(antibiotic resistance genes, ARGs)污染问题日益严峻，对畜禽健康养殖和公共卫生安全构成威胁^[1]。Naghavi等^[2]开展的一项覆盖全球204个国家和地区的研究表明，2021年因抗生素抗性菌(antibiotic resistance bacteria, ARB)感染问题直接或间接导致多达127万人和495万人死亡，预计到2050年这一数字将达到191万人和822万人。如何控制ARGs的传播，从而降低其对人和动物的健康风险已成为热点问题。

细菌通常可通过2种主要方式传播ARGs，即通过亲代复制的垂直基因转移(vertical gene transfer, VGT)和可移动遗传元件(mobile genetic elements, MGEs)介导的水平基因转移(horizontal gene transfer, HGT)^[3-4]。细菌获得ARGs虽能抵抗药物，但通常会产生一定的适应性代价，即在无抗生素环境下ARB相对于敏感菌表现出明显的竞争劣势^[5]。适应性代价会影响ARGs在菌群中的传播，例如降低其接合转移能力，并在停用抗生素后加快ARGs的丢失速度^[6]。适应性代价的研究可为抑制ARB提供新线索，但当前仍面临诸多挑战。例如，适应性代价的精确测量方法、适应性代价与抗生素抗性(antibiotic resistance, AR)的关系以及分子机制仍不明确。解决这些问题对于控制ARB至关重要。本文将探讨适应性代价的产生机制和测量方法，说明不同获得方式下ARGs介导的适应性代价，介绍染色体和质粒介导ARGs的适应性代价差异及分子机制，最后提出临床应用的启示和未来研究方向，以期为从适应性代价角度遏制ARB提供科学思路。

1 抗生素抗性菌的适应性代价

收起

1.1 适应性代价的定义及产生机制

适应性是指细菌通过适当调节自身代谢以适应生存环境，并具备较好繁殖能力的过程，通常涉及生长力、侵袭力、致病力的变化^[7]。细菌在获得ARGs后能够适应抗生素胁迫下的环境，在有抗生素的环境中继续生长繁殖并持续存在，其竞争能力优于敏感菌株；然而在无抗生素环境中ARGs反而成为细菌的负担，导致其生长代谢、运动能力、毒力、生物膜形成能力下降，这就是ARB的适应性代价^[5]。因此，研究适应性代价对于理解菌群中AR的发展和持久性至关重要，是决定ARGs在环境中存在和传播的关键因素^[8]。

适应性代价的产生机制与ARGs的获得方式以及抗性机制密切相关。菌株除通过VGT获得ARGs外，还可通过2种主要途径获得ARGs：(1) 通过基因突变获得ARGs^[3]；(2) 通过HGT获得ARGs^[4]。通过基因突变获得的ARGs通常会使细菌的基因编码效率降低、相应表达蛋白的活性降低，扰乱细菌的正常代谢或生物功能，导致细菌的整体适应能力下降，从而造成适应性代价^[9]。在HGT途径中MGEs介导的ARGs传播通常会产生多维度适应性代价：(1) 抗生素抗性质粒的接合转移过程复杂，需要供体与受体大量蛋白的协调表达和调控，且会大量占用细胞器并消耗能量^[10]；(2) 携带ARGs的质粒在胞内的复制、转录和翻译均需消耗额外的能量和资源，使细菌产生额外的遗传和代谢负担^[11-12]；(3) 在某些情况下，整合酶催化整合子与基因盒之间的重组反应，可能引发非典型位点的重组事件，导致宿主基因组不稳定^[13]；(4) 转座子可通过产生有害突变和破坏配子发生，从而对其宿主施加适应性代价^[14]。ARGs的抗性机制包括降低抗生素的渗透性、抗生素的主动运输、抗生素靶标改变与保护、抗生素的灭活与修饰以及靶标旁路途径^[15]，由于这些抗性机制的分子机制不同，细菌所表现的适应性代价也存在差异。

1.2 适应性代价的测量方法

细菌适应性代价的测量方法(图1)主要包括生长曲线(growth curves)法和竞争试验法。生长曲线法主要是在体外相同条件下单独培养抗性菌和敏感菌，测定吸光度并绘制生长曲线图，以确定不同菌株的生长能力，并通过比较二者的生长速度差异来测量适应性代价^[16]。竞争试验是将抗性菌和敏感菌共同培养，比较二者在相同环境下的生长和存活能力，通过测定一定时间内二者的数量和比例变化，计算相对适应性(relative fitness, RF)或选择系数(selection coefficient, S)来测量适应性代价。竞争试验主要包括2种：(1) 体内竞争试验，通常在实验动物或设计的动物感染模型内进行培养，通过感染动物或模型来测量ARB的适应性代价^[17]；(2) 体外试验，通常在培养基中进行，将抗性菌与敏感菌按一定比例混合，在无抗生素的条件下进行共培养以竞争营养资源^[18]。在开展生长曲线测定和竞争实验的基础上，为系统评估适应性代价，需进一步测定生长代谢、运动能力、毒力、生物膜形成等指标。

竞争试验法广泛用于测量适应性代价，是测量适应性代价的“黄金标准”^[5]。相较于测量生长曲线，竞争试验考虑了菌株之间在不同生长阶段的相互作用，并能多方面描述菌株全部生长周期的生物学特性^[19]。体外竞争试验通常在培养基中进行，实验条件相对容易控制、操作方便、易于实现且无需考虑动物福利，同时可快速进行，因而较为常用^[20]；相较于体外竞争试验，体内竞争试验相对不可控、成本高，但可得到真实感染情况下的适应性变化，对于研究病原体和宿主之间的相互作用具有重要意义，是评估安全性和有效性的最佳选择^[20]。对比二者的实验结果存在巨大差异，例如，Evangelopoulos等^[21]发现大多数d-环丝氨酸抗性菌在小鼠体内试验时检测到适应性显著降低，仅通过体外试验无适应性代价的表现，无法发现宿主对ARB的胁迫作用。蔡文慧^[22]通过体内外实验发现，携带H-NS蛋白的lncX1型tet(X4)阳性质粒在小鼠体内具有很高的适应性，且普遍优于体外的研究结果。刘德俊^[23]通过体外生长试验发现，弯曲杆菌属(Campylobacter)携带ermB基因后生长、定殖能力降低；而在肉鸡体内竞争试验中，抗性菌在接种初期表现出菌毛合成异常和能量代谢失衡，导致适应性降低。

除经典的适应性代价测量方法外，还可以根据流行病数据建立数学模型来衡量适应性代价，其能在一定程度上突破实验限制，从而客观反映抗生素使用与抗性变化的联系。例如，Ram等^[24]开发出一种基于单一培养物和混合培养物的生长曲线，能够预测混合培养物相对生长的方法；Helekal等^[25]将多谱系流行病学模型与系统发育合并理论结合，根据基因组数据估计ARB的适应性代价。此外，数学模型可以根据适应性代价的高低预测ARGs下降的速率，但由于某些细菌表现为无适应性代价以及补偿性进化(compensatory evolution)途径的存在，导致数学模型法的参数计算无法考虑真实情况的所有因素，存在统计学上的偏差，使模型不能满足实际情况^[26]，并且开发数学模型用于适应性代价评估依赖较大的数据集和计算成本，这些因素都限制了模型开发。

1.3 不同获得方式下ARGs介导的适应性代价

由于细菌获得AR的方式和抗性机制多种多样，且其表现的适应性代价不尽相同，AR与适应性代价之间存在复杂的关系。本节总结了近年来关于细菌AR与适应性代价的相关研究(表1)，这些研究通过测定生长曲线、开展竞争试验以及构建动物模型等途径，以测定和计算生长曲线(growth curves)之间的显著差异(P)、相对适应度(relative fitness, RF)、选择系数(S)等指标的方式评价了不同细菌、不同抗生素抗性机制下的适应性代价。其中，细菌通过转化和胞外囊泡方式获得AR而引起的适应性代价的研究较少，未在表1中列举。

获得ARGs会影响细菌的运动能力、毒力、ARGs的传播速度和竞争能力，使细菌表现出适应性代价。在由基因突变产生的ARGs中利福平抗性基因rpoB突变显著延长表皮葡萄球菌(Staphylococcus epidermidis)的复制周期^[27]，铜绿假单胞菌(Pseudomonas aeruginosa)的多药物外排泵基因nfxB突变导致能量代谢负荷增加^[28]，耻垢分枝杆菌(Mycobacterium smegmatis) rv2752c突变通过降低RNA聚合酶转录效率引起全局基因表达下调，从而使细菌生长速度变慢^[29]。在细菌通过HGT获得的ARGs中，适应性代价表现为携带β-内酰胺类酶基因bla_CTX-M-14、bla_NDM和bla_CTX-M-55导致大肠埃希氏菌(Escherichia coli)丧失接合转移能力^[30]以及毒力^[31]和生长速度^[38]下降；携带sul3导致大肠埃希氏菌运动能力下降^[34]；转座子介导粪肠球菌(Enterococcus faecalis)获得万古霉素抗性基因vanA增加了细菌的基因表达负担^[35]；携带dfrA1-sat2-aadA1抗性基因盒的大肠埃希氏菌生长速度下降^[36]。

部分细菌获得ARGs后并未表现出显著的适应性代价，甚至适应性得到了提高。例如，铜绿假单胞菌DNA旋转酶基因gyrA、gyrB的抗性突变^[28]和大肠埃希氏菌通过接合转移获得喹诺酮类抗性基因qnrA、qnrB、qnrS^[32]；沙门氏菌(Salmonella)通过接合转移获得磷霉素抗性基因fosA7也表现出无适应性代价^[33]；大肠埃希氏菌通过转座子获得磺胺类抗性基因sul1和sul2^[34]。通过噬菌体转导获得ARGs提高了细菌的适应性，酿脓链球菌(Streptococcus pyogenes)携带Φm46.1噬菌体转导的大环内酯类和四环素类抗性基因mef(A)、tet(O)^[37]，以及大肠埃希氏菌携带P1噬菌体转导的β-内酰胺类酶基因bla_CTX-M-55^[38]，均提高了细菌的生长速率。

2 染色体和质粒介导的ARGs的适应性代价差异及分子机制

收起

ARGs会给细菌带来适应性代价，深入解析适应性代价背后的分子机制有助于更加全面、系统地认识ARB的特性。在抗生素胁迫下，细菌可通过染色体基因突变和HGT方式获得ARGs，其中质粒是MGEs介导ARGs发生HGT的重要载体^[39]。因此，本节将聚焦于染色体和质粒介导的ARGs的适应性代价。由于ARGs种类和抗性机制不同，染色体和质粒介导的ARGs的适应性代价有所区别(表2)。

2.1 染色体介导的ARGs的适应性代价

位于染色体上的ARGs引起的适应性代价与抗性机制相关联。目前已知的抗生素抗性机制包括降低外膜渗透性、抗生素的主动外排和修饰抗生素靶标等。

细菌通过下调孔蛋白通透性来降低外膜渗透性，从而减少各种抗生素进入细胞，这是引起革兰氏阴性菌多重抗性的主要原因之一^[65]。例如，常见的ompC/F孔蛋白基因表达下调将导致细菌吸收各种物质受阻，生长缓慢^[40]。当氨基酸缺乏，RelA蛋白感知空载tRNA时细菌会过表达鸟苷四磷酸以增强DNA甲基化酶催化复制起点与终点的GATC甲基化，该甲基化序列与SqeA蛋白结合而引发复制停滞^[41]。孔蛋白表达下调会引起细菌csgA和csgB基因表达下调，进而导致卷曲菌毛(curli)合成下降^[42]，最终使生物膜形成受到抑制^[43]。

细菌染色体编码的外排泵能将多种抗生素排至胞外，使细菌具有多重抗性，这些外排泵主要是抗性结节分化家族(resistance nodulation division, RND)，且常见于革兰氏阴性菌。细菌外排泵的过表达不仅会增加能量消耗，还会泵出细菌代谢物，如群体感应(quorum sensing, QS)信号，影响菌群的代谢^[15]。例如，铜绿假单胞菌过表达mexABOprM和mexCDOprJ会减少吩嗪类毒力因子的合成，并影响QS系统rhl，进而引起MexA蛋白缺乏，导致毒力下降^[44]；铜绿假单胞菌过表达mexEFOprN编码的外排泵MexEF-OprN会泵出HHQ分子(PQS前体)导致PQS信号分子产生延迟，且降低细菌的毒力^[45]；此外，该外排泵可作为质子反向转运体，其过表达可导致细胞内H⁺积累，从而影响胞内pH的稳态，对细菌造成伤害^[46]。不同外排泵的过表达对生物膜形成能力的影响不同，鲍氏不动杆菌(Acinetobacter baumannii)过表达ade类外排泵会引起CsuA/B、CsuC和FimA菌毛蛋白以及OmpA外膜结构蛋白下调，从而导致生物膜形成能力下降^[47]；鼠伤寒沙门氏菌过表达acrABTolC会促进QS信号AHL与SdiA膜受体结合，进而促进生物膜形成^[48]。

细菌可修饰或改变抗生素的靶标从而使抗生素失效，这类情况主要涉及氨基糖苷类和利福平药物。染色体介导的rRNA基因位点突变的适应性代价更为严重。例如，16S rRNA基因的A1408位点突变为嘌呤G时无明显的适应性代价；若突变为嘧啶C/U则会导致氨酰基-tRNA解码位点(A位点)形成稳定的碱基堆叠，难以完成ON/OFF切换，使翻译受到抑制，最终造成细菌死亡^[49]。rpoB突变介导RNA聚合酶的保守结构改变，虽然阻断了利福平与β亚基结合，但也损害了细菌的转录水平^[6,50]。

2.2 质粒介导的ARGs的适应性代价

质粒介导的ARGs的适应性代价也与抗性机制相关。细菌编码可对抗生素的结构进行修饰或降解的酶，从而使抗生素失去活性^[15]，此类基因在β-内酰胺类抗生素中较常见，如pLVPK(IncFII)-bla_KPC-2^[51]、pUCP-FOX-8(IncQ)-bla_FOX-4/8^[52]、p210704-1(IncC)-bla_NDM以及p210744-5(IncX3)-bla_NDM^[11]，在四环素类抗生素中也较常见，如pUC19-tetX^[53-54]以及tet(X4)^[55]。细菌表达β-内酰胺酶可造成细菌的iucA、magA和rmpA2毒力基因下调^[51]以及AmpC酶高表达，干扰细胞壁完整性，导致成毒力下降^[52]，还会使细菌的运动和复制能力下降^[11]。催化四环素氧化的四环素灭活酶，如tet(X)家族，可引起atlR基因下调，无法抑制质粒的拷贝数，导致细菌生物膜形成和毒力下降^[53]，因而提高ATP酶活性和蛋白质合成，增大代谢负担^[54]。此外，在大肠埃希氏菌携带的20个不同tet(X4)阳性质粒中大部分质粒表现出适应性代价，但pRF154-1(IncFII)、pRS3-1(IncFIB)和pRF55-1(IncX1)这3个质粒显著促进了生物膜的产生，IncFIA和IncX1型质粒表现出毒力增强，可能是这些质粒携带了生物膜形成和毒力基因^[55]。

质粒可携带特定药物的外排泵基因，其过表达会引起适应性代价。对于携带四环素类药物外排泵基因的情况，嗜油不动杆菌(Acinetobacter oleivorans)过表达pAST2-tetH会引起fimA和fimC菌毛基因下调，导致运动性缺陷^[56]；大肠埃希氏菌携带并表达pBR322-tetA，因Trk转运系统对K⁺的吸收效率降低会增加能量消耗^[57]。对于携带喹诺酮类药物外排泵的情况，大肠埃希氏菌表达pBK-CMV-qepA2表现为无适应性代价，当该基因引起位于染色体上的gyrA和parC突变时细菌的相对适应性降低(RF<1)，并通过marR缺失进行补偿^[58]；而大肠埃希氏菌携带pHNGC59(IncF)-oqxAB和pHNFD436(IncX3)-oqxAB时相对适应性低(0.873和0.764)，当这引起位于染色体上的gyrAB突变时相对适应性却升高(RF>1)^[59]。

质粒携带修饰抗生素靶标[如肽聚糖、核糖体和脂多糖(lipopolysaccharide, LPS)]的ARGs，其适应性代价与修饰位点有关。革兰氏阳性菌表达pJAK112-van基因可修饰肽聚糖与糖肽类抗生素结合的d-Ala-d-Ala位点，但因其孢子形成缺陷而导致感染能力下降^[60]。pGB2(IncP-1)-armA与pGB2(IncP-1)-npmA对16S rRNA基因的G1405和A1408位点进行抗性甲基化时无适应性代价，但这会干扰A位点C1402和C1407的内源甲基化，降低核糖体翻译效率^[61]。pJAK112-cfr的表达对23S rRNA基因A2503位点的抗性甲基化无适应性代价，但当ermB启动子驱动ermB与cfr基因共表达时会导致A2508位点发生二甲基化，这2个位点位于核糖体的肽链出口隧道，会干扰翻译功能^[62]。pBBR1MCS-5-mcr-1介导革兰氏阴性菌的LPS的脂质A被带正电荷的残基(如磷酸乙醇胺或氨基阿拉伯糖)修饰，从而阻止多黏菌素破坏细菌的细胞壁，但会引起脂质A的合成受损^[63]。Lu等^[64]对大肠埃希氏菌过表达pHNSPH24(IncFII)-mcr-1的转录组学研究发现，waa和rml基因下调引起细菌LPS核心和O抗原合成下调，导致细胞膜通透性增强和膜去极化，此外还影响碳水化合物代谢、氧化应激与DNA损伤，以及ABC转运蛋白下调。

3 基于适应性代价的ARB防控策略

收起

3.1 适应性代价的靶向干预

利用适应性代价干预抗性菌的核心思路是通过靶向调控相关基因的表达水平人为增加其生存成本，从而在无抗生素压力的环境中加速ARB的淘汰(图2)。(1) 根据调控基因的靶向代谢物类似物的错误代谢诱导来加剧适应性代价：携带他伐硼罗抗性基因leuS的大肠埃希氏菌无法分离非亮氨酸与亮氨酸tRNA之间的错误连接，导致蛋白质合成异常，最终表现为生长缓慢，因此采用高度敏感的亮氨酸类似物(如正缬氨酸)能提高其错误率以增强其适应性代价^[66]。携带利福平抗性的rpoB H526Y突变体大肠埃希氏菌，其upp基因参与尿嘧啶的回收利用，使转录效率显著升高，干扰细菌正常的转录调控，因此使用高度敏感的尿嘧啶类似物(如5-氟尿嘧啶)能够干扰抗性菌的转录以加剧其适应性代价^[67]。(2) 通过调节调控基因来加剧适应性代价：抗利福平药物的rpoB H526Y突变体大肠埃希氏菌，其gpp基因的编码产物能降解信号分子ppGpp，使高转录效率无法被有效抑制，基于该菌的RNA聚合酶对ppGpp不敏感的特性，抑制gpp基因不会调控细菌转录效率，反而会使其细胞壁合成缺陷，从而加剧了适应性代价^[67]。mcr-1表达会诱导活性氧(reactive oxygen species, ROS)产生，ROS会激活dinB，通过负反馈抑制mcr-1的转录和翻译，从而增强大肠埃希氏菌的适应性，所以通过抑制dinB能降低mcr-1阳性菌的毒性和适应性^[68]。(3) 利用细菌对抗生素的附带敏感性(collateral sensitivity)，即当细菌因基因突变或适应环境而对某种药物产生抗性时会表现出相应的适应性代价，反而对另一种不同作用机制的药物变得更加敏感的特性^[69]。例如，nfxB突变体铜绿假单胞菌过表达MexCD-OprJ外排泵从而产生对喹诺酮药物的抗性，但MexD蛋白会竞争性替代MexXY-OprM外排泵的MexY蛋白，而MexX蛋白相互作用，这减弱了MexXY-OprM外排泵对特异性底物氨基糖苷类抗生素的外排功能^[70]。大肠埃希氏菌发生rfaH、rfaG和envZ基因突变，从而产生对头孢菌素药物的抗性，但也表现出苏氨酸-tRNA连接酶合成缺陷和外膜不稳定性的适应性代价，使细菌对博来霉素药物的抗性下降^[71]。金黄色葡萄球菌(Staphylococcus aureus)的apmA基因表达对安普霉素产生抗性，但也导致编码青霉素结合蛋白PBP2a的mecA基因表达下调、β-内酰胺酶活性降低和质子动力势紊乱引起外排泵活性丧失的适应性代价，使细菌对β-内酰胺类药物的抗性下降^[72]。

3.2 补偿性进化的分子阻断策略

补偿性进化是指ARB通过基因突变或非突变途径来提高适应性，从而降低或消除适应性代价，是细菌适应性进化的一种方式，在有无抗生素存在的情况下均可发生，主要包括二次突变、正向异位显性效应、基因重复和非突变性补偿4种类型，这增加了控制ARB的难度^[73-74]。因此可以靶向补偿性进化的位点，设计药物或进行基因敲除加以干预(图2)。例如，Balbontín等^[75]发现，发生双抗性突变的细菌容易引起转录-翻译冲突而产生R环，其可被通过补偿性进化的细菌表达的Rnase HI降解，因此可通过该酶抑制剂RHI001或基因敲除来抑制细菌DNA断裂修复。Olivares Pacheco等^[46]发现，RND外排泵过表达会导致胞内H⁺积累，需要通过增大耗氧量以及表达硝酸盐呼吸链进行代谢补偿以将其消除，因此可通过降低氧气和硝酸盐的供应，以及使用硝酸盐呼吸链抑制剂来阻断该补偿机制。Wen等^[76]通过代谢组学分析发现，在亚最低抑菌浓度(minimum inhibitory concentration, MIC)下的强力霉素抗性大肠埃希氏菌通过下调丙酮酸以减少旁路碳代谢，下调毛果芸香碱以抑制次级代谢，从而减缓适应性代价，因此可通过下调二者的表达来阻断该补偿途径。Freihofer等^[77]发现结核分枝杆菌(Mycobacterium tuberculosis)发生16S rRNA基因的A1408G位点突变会引起生长缓慢的适应性代价，其可通过增强tlyA基因表达以促进C1409位点甲基化，从而降低适应性代价，因此通过使用卷曲霉素可诱导该基因失活。

4 总结与展望

收起

细菌通过基因突变或水平基因转移获得ARGs时普遍伴随代谢负担、运动性、生物膜形成能力和毒力下降等适应性代价。适应性代价是自然环境中阻碍ARGs传播的关键生物学因素。本文围绕适应性代价进行了系统总结：阐述了适应性代价的核心产生机制及经典测量方法，明确了不同测量手段的优势与局限；针对ARGs的不同获得方式、不同载体(染色体、质粒)系统讨论了其对适应性代价的差异化影响及机制；基于上述机制，提出了根据适应性代价的靶向干预与补偿性进化的分子阻断这2种ARB防控策略，为从“适应性权衡”角度遏制ARGs传播提供了科学依据。

先前的研究多聚焦于细菌的AR问题，而对人类社会而言，目前更迫切需要比研发新型抗生素更简便、低成本和高效的方法。因此可以从ARB的适应性机制入手解析适应性代价的具体表现，挖掘影响适应性代价的关键因素，并基于适应性代价机制设计干预策略，尤其是针对致病菌的AR问题及其携带的高风险ARGs (如万古霉素、替加环素、碳青霉烯类抗生素抗性基因等)所引起的适应性代价。

基金

收起

国家自然科学基金(32402820)
国家现代农业产业技术体系(CARS-40)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

ASLAM

, WANG

, ARSHAD

, KHURSHID

, MUZAMMIL

, RASOOL

, NISAR

, ALVI

, ASLAM

, QAMAR

, SALAMAT

MKF

, BALOCH

. Antibiotic resistance: a rundown of a global crisis[J]. Infection and Drug Resistance, 2018, 11: 1645-1658.

[2]

NAGHAVI

, VOLLSET

, IKUTA

, SWETSCHINSKI

, GRAY

, WOOL

, ROBLES AGUILAR

, MESTROVIC

, SMITH

, HAN

, HSU

, CHALEK

, ARAKI

, CHUNG

, RAGGI

, GERSHBERG HAYOON

, DAVIS WEAVER

, LINDSTEDT

, SMITH

, ALTAY

, et al. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050[J]. The Lancet, 2024, 404(10459): 1199-1226.

[3]

GIEDRAITIENĖ

, VITKAUSKIENĖ

, NAGINIENĖ

, PAVILONIS

. Antibiotic resistance mechanisms of clinically important bacteria[J]. Medicina, 2011, 47(3): 137-146.

[4]

ARNOLD

, HUANG

, HANAGE

. Horizontal gene transfer and adaptive evolution in bacteria[J]. Nature Reviews Microbiology, 2021, 20(4): 206-218.

[5]

MELNYK

, WONG

, KASSEN

. The fitness costs of antibiotic resistance mutations[J]. Evolutionary Applications, 2015, 8(3): 273-283.

[6]

, PRESTON

, MacLEAN

. Linking system-wide impacts of RNA polymerase mutations to the fitness cost of rifampin resistance in Pseudomonas aeruginosa [J]. mBio, 2014, 5(6): e01562.

[7]

ANDERSSON

. The biological cost of mutational antibiotic resistance: any practical conclusions?[J]. Current Opinion in Microbiology, 2006, 9(5): 461-465.

[8]

SHERRARD

, BA

WEE

, DUPLANCIC

, RAMSAY

, DAVE

, BALLARD

, WAINWRIGHT

, GRIMWOOD

, SIDJABAT

, WHILEY

, BEATSON

, KIDD

, BELL

. Emergence and impact of oprD mutations in Pseudomonas aeruginosa strains in cystic fibrosis[J]. Journal of Cystic Fibrosis, 2022, 21(1): e35-e43.

[9]

KNÖPPEL

, NÄSVALL

, ANDERSSON

. Compensating the fitness costs of synonymous mutations[J]. Molecular Biology and Evolution, 2016, 33(6): 1461-1477.

[10]

CURTSINGER

, MARTÍNEZ-ABSALÓN

, LIU

, LOPATKIN

. The metabolic burden associated with plasmid acquisition: an assessment of the unrecognized benefits to host cells[J]. BioEssays, 2025, 47(2): e2400164.

[11]

ZHANG

, XU

, HE

, HAN

, QU

. Characterization and fitness cost analysis of two plasmids carrying different subtypes of bla_NDM in aquaculture farming[J]. Food Microbiology, 2023, 115: 104327.

[12]

RAJER

, SANDEGREN

. The role of antibiotic resistance genes in the fitness cost of multiresistance plasmids[J]. mBio, 2022, 13(1): e0355221.

[13]

LACOTTE

, PLOY

, RAHERISON

. Class 1 integrons are low-cost structures in Escherichia coli [J]. The ISME Journal, 2017, 11(7): 1535-1544.

[14]

KELLEHER

, AZEVEDO

RBR

, ZHENG

. The evolution of small-RNA-mediated silencing of an invading transposable element[J]. Genome Biology and Evolution, 2018, 10(11): 3038-3057.

[15]

DARBY

, TRAMPARI

, SIASAT

, GAYA

, ALAV

, WEBBER

, BLAIR

JMA

. Molecular mechanisms of antibiotic resistance revisited[J]. Nature Reviews Microbiology, 2022, 21(5): 280-295.

[16]

HUANG

. Optimization of a new mathematical model for bacterial growth[J]. Food Control, 2013, 32(1): 283-288.

[17]

ANDERSSON

, HUGHES

. Antibiotic resistance and its cost: is it possible to reverse resistance?[J]. Nature Reviews Microbiology, 2010, 8(4): 260-271.

[18]

DelaFUENTE

, RODRIGUEZ-BELTRAN

, MILLAN A

SAN

. Methods to study fitness and compensatory adaptation in plasmid-carrying bacteria[J]. Methods in Molecular Biology, 2020, 2075: 371-382.

[19]

WISER

, LENSKI

. A comparison of methods to measure fitness in Escherichia coli [J]. PLoS One, 2015, 10(5): e0126210.

[20]

SHI

, MI

, WANG

, WEBSTER

. In vitro and ex vivo systems at the forefront of infection modeling and drug discovery[J]. Biomaterials, 2019, 198: 228-249.

[21]

EVANGELOPOULOS

, PROSSER

, RODGERS

, DAGG

, KHATRI

, HO MM, GUTIERREZ

, CORTES

, de CARVALHO

LPS

. Comparative fitness analysis of d-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes[J]. Nature Communications, 2019, 10: 4177.

[22]

蔡文慧. H-NS蛋白对tet(X4) lncX1型质粒在革兰阴性菌中的适应性的调节[D]. 扬州: 扬州大学, 2022.

CAI

. Histone-like nucleoid structuring protein modulates the fitness of tet(X4)-bearing lncX1 plasmids in Gram-negative bacteria[D]. Yangzhou: Yangzhou University, 2022 (in Chinese).

[23]

刘德俊. 携带ermS基因畜禽源弯曲菌的流行及适应性机制的研究[D]. 北京: 中国农业大学, 2017.

LIU

. Studies on prevalence and fitness mechanisms of ermS-positive Campylobacter from livestock and poultry[D]. Beijing: China Agricultural University, 2017 (in Chinese).

[24]

RAM Y, DELLUS-GUR

, BIBI

, KARKARE

, OBOLSKI

, FELDMAN

, COOPER

, BERMAN

, HADANY

. Predicting microbial growth in a mixed culture from growth curve data[J]. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(29): 14698-14707.

[25]

HELEKAL

, KEELING

, GRAD

, DIDELOT

. Estimating the fitness cost and benefit of antimicrobial resistance from pathogen genomic data[J]. Journal of the Royal Society, Interface, 2023, 20(203): 20230074.

[26]

CARD

, JORDAN

, LENSKI

. Idiosyncratic variation in the fitness costs of tetracycline-resistance mutations in Escherichia coli [J]. Evolution, 2021, 75(5): 1230-1238.

[27]

WI YM, GREENWOOD-QUAINTANCE

, BRINKMAN

, LEE

JYH

, HOWDEN

, PATEL

. Rifampicin resistance in Staphylococcus epidermidis: molecular characterisation and fitness cost of rpoB mutations[J]. International Journal of Antimicrobial Agents, 2018, 51(5): 670-677.

[28]

MELNYK

, McCLOSKEY

, HINZ

, DETTMAN

, KASSEN

. Evolution of cost-free resistance under fluctuating drug selection in Pseudomonas aeruginosa [J]. mSphere, 2017, 2(4): e00158-17.

[29]

马鹏娇. 结核分枝杆菌药物耐受及利福平耐药补偿机制研究[D]. 成都: 四川大学, 2021.

. The mechanism of drug tolerance and compensation for rifampicin resistance in Mycobacterium tuberculosis [D]. Chengdu: Sichuan University, 2021 (in Chinese).

[30]

DIMITRIU

, MEDANEY

, AMANATIDOU

, FORSYTH

, ELLIS

, RAYMOND

. Negative frequency dependent selection on plasmid carriage and low fitness costs maintain extended spectrum β-lactamases in Escherichia coli [J]. Scientific Reports, 2019, 9: 17211.

[31]

刘子奕. 耐碳青霉烯肠杆菌的分子流行特征及bla_NDM阳性质粒适应性进化机制研究[D]. 扬州: 扬州大学, 2023.

LIU

. Molecular epidemic characteristics of carbapenem-resistant Enterobacterales and the adaptive evolutionary mechanism of bla_NDM-bearing plasmid[D]. Yangzhou: Yangzhou University, 2023 (in Chinese).

[32]

兰芳俊. qnr基因对细菌喹诺酮耐药突变选择窗及其适应性代价影响的研究[D]. 福州: 福建医科大学, 2018.

LAN

. Study of qnr gene to mutant selection window and the effects of fitness cost on bacterial quinolone resistance[D]. Fuzhou: Fujian Medical University, 2018 (in Chinese).

[33]

王燕. 耐药基因fosA7在沙门菌分离株的流行特征及适应性研究[D]. 扬州: 扬州大学, 2021.

WANG

. Epidemiological characteristics and fitness of the resistant gene fosA7 in Salmonella isolates[D]. Yangzhou: Yangzhou University, 2021 (in Chinese).

[34]

方结红. 生猪屠宰厂大肠杆菌磺胺耐药基因sul1、sul2和sul3的传播与适应性机制研究[D]. 杭州: 浙江工商大学, 2018.

FANG

. Research on the dissemination and fitness mechanism of Escherichia coli sulfonamide-resistant genes sul1, sul2 and sul3 in a pig slaughterhouse[D]. Hangzhou: Zhejiang Gongshang University, 2018 (in Chinese).

[35]

KIM

, KANG

, CHOI

, HONG

, KIM

, UH Y, SHIN

, SHIN

, KIM

, SHIN

, JEONG

. Fitness costs of Tn1546-type transposons harboring the vanA operon by plasmid type and structural diversity in Enterococcus faecium [J]. Annals of Clinical Microbiology and Antimicrobials, 2024, 23(1): 62.

[36]

焦雪, 余庭, 方结红, 唐标, 汪雯, 蒋晗. 水产源大肠杆菌耐药可移动遗传元件Ⅱ型整合子的结构特征及适应性代价[J]. 中国食品学报, 2022, 22(4): 25-33.

JIAO

, YU

, FANG

, TANG

, WANG

, JIANG

. Structural characteristic and fitness cost of the drug-resistant mobile genetic elements class II integrons of Escherichia coli from aquatic food[J]. Journal of Chinese Institute of Food Science and Technology, 2022, 22(4): 25-33 (in Chinese).

[37]

GIOVANETTI

, BRENCIANI

, MORRONI

, TIBERI

, PASQUAROLI

, MINGOIA

, VARALDO

. Transduction of the Streptococcus pyogenes bacteriophage Φm46.1, carrying resistance genes mef(A) and tet(O), to other Streptococcus species[J]. Frontiers in Microbiology, 2015, 5: 746.

[38]

蒋黎. 多耐药P1-like噬菌体质粒的遗传特征及转导bla_CTX-M-55传播的形成机制[D]. 扬州: 扬州大学, 2024.

JIANG

. Genetic characterization of a multiresistant P1-like phage plasmid and the formation mechanism of transducing bla_CTX-M-55 propagation[D]. Yangzhou: Yangzhou University, 2024 (in Chinese).

[39]

SEOANE

, YANKELEVICH

, DECHESNE

, MERKEY

, STERNBERG

, SMETS

. An individual-based approach to explain plasmid invasion in bacterial populations[J]. FEMS Microbiology Ecology, 2011, 75(1): 17-27.

[40]

SCHÄFER

, GÖRNER

, WOLTEMATE

, BRANDENBERGER

, GEFFERS

, ZIESING

, SCHLÜTER

, VITAL

. The resistance mechanism governs physiological adaptation of Escherichia coli to growth with sublethal concentrations of carbapenem[J]. Frontiers in Microbiology, 2022, 12: 812544.

[41]

FERULLO

, LOVETT

. The stringent response and cell cycle arrest in Escherichia coli [J]. PLoS Genetics, 2008, 4(12): e1000300.

[42]

TRAMPARI

, ZHANG

, GOTTS

, SAVVA

, BAVRO

, WEBBER

. Cefotaxime exposure selects mutations within the CA-domain of envZ which promote antibiotic resistance but repress biofilm formation in Salmonella [J]. Microbiology Spectrum, 2022, 10(3): e0214521.

[43]

陆利, 曹保华, 王义强. 大肠杆菌CFT073中Curli系统重要基因csgF的克隆、表达、纯化和结构分析[J]. 微生物学通报, 2016, 43(9): 2063-2071.

, CAO

, WANG

. Expression, purification and structural analysis of csgF gene of curli systems from Escherichia coli CFT073[J]. Microbiology China, 2016, 43(9): 2063-2071 (in Chinese).

[44]

SÁNCHEZ

, LINARES

, RUIZ-DÍEZ

, CAMPANARIO

, NAVAS

, BAQUERO

, MARTÍNEZ

. Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants[J]. Journal of Antimicrobial Chemotherapy, 2002, 50(5): 657-664.

[45]

OLIVARES

, ALVAREZ-ORTEGA

, LINARES

, ROJO

, KÖHLER

, MARTÍNEZ

. Overproduction of the multidrug efflux pump MexEF-OprN does not impair Pseudomonas aeruginosa fitness in competition tests, but produces specific changes in bacterial regulatory networks[J]. Environmental Microbiology, 2012, 14(8): 1968-1981.

[46]

OLIVARES PACHECO

, ALVAREZ-ORTEGA

, ALCALDE RICO

, MARTÍNEZ

. Metabolic compensation of fitness costs is a general outcome for antibiotic-resistant Pseudomonas aeruginosa mutants overexpressing efflux pumps[J]. mBio, 2017, 8(4): e00500-17.

[47]

YOON

, BALLOY

, FIETTE

, CHIGNARD

, COURVALIN

, GRILLOT-COURVALIN

. Contribution of the Ade resistance-nodulation-cell division-type efflux pumps to fitness and pathogenesis of Acinetobacter baumannii [J]. mBio, 2016, 7(3): e00697-16.

[48]

DAWAN

, LI

, LU

, HE

, AHN J. Role of efflux pump-mediated antibiotic resistance in quorum sensing-regulated biofilm formation by Salmonella typhimurium [J]. Pathogens, 2022, 11(2): 147.

[49]

KONDO

, KOGANEI

. Structural bases for the fitness cost of the antibiotic-resistance and lethal mutations at position 1408 of 16S rRNA[J]. Molecules, 2020, 25(1): 159.

[50]

HALL

, ILES

, MacLEAN

. The fitness cost of rifampicin resistance in Pseudomonas aeruginosa depends on demand for RNA Polymerase[J]. Genetics, 2011, 187(3): 817-822.

[51]

刘周. 高毒力肺炎克雷伯菌分子特征、碳青霉烯耐药机制及进化相关适应性代价研究[D]. 合肥: 安徽医科大学, 2019.

LIU

. Study on molecular characteristics, carbapenem resistance mechanism and evolution-related fitness cost of hypervirulent Klebsiella pneumoniae [D]. Hefei: Anhui Medical University, 2019 (in Chinese).

[52]

BARCELÓ

, JORDANA-LLUCH

, ESCOBAR-SALOM

, TORRENS

, FRAILE-RIBOT

, CABOT

, MULET

, ZAMORANO

, JUAN

, OLIVER

. Role of enzymatic activity in the biological cost associated with the production of AmpC β-lactamases in Pseudomonas aeruginosa [J]. Microbiology Spectrum, 2022, 10(5): e0270022.

[53]

江礼捷. tet(X4)介导的高水平替加环素耐药性的适应性代价研究[D]. 扬州: 扬州大学, 2022.

JIANG

. Investigation of the fitness cost of tet(X4)-mediated high-level tigecycline resistance[D]. Yangzhou: Yangzhou University, 2022 (in Chinese).

[54]

CHEN

, ZHAO

, TANG

, WEI

, WEN

, ZHOU

, MA

, ZOU

, ZHANG

, MI

, WANG

, LIAO

, WU

. The tigecycline resistance gene tetX has an expensive fitness cost based on increased outer membrane permeability and metabolic burden in Escherichia coli [J]. Journal of Hazardous Materials, 2023, 458: 131889.

[55]

TANG

, CAI

, JIANG

, WANG

, LIU

. Large-scale analysis of fitness cost of tet(X4)-positive plasmids in Escherichia coli [J]. Frontiers in Cellular and Infection Microbiology, 2022, 12: 798802.

[56]

HONG

, JUNG

, PARK

. Plasmid-encoded tetracycline efflux pump protein alters bacterial stress responses and ecological fitness of Acinetobacter oleivorans [J]. PLoS One, 2014, 9(9): e107716.

[57]

HELLWEGER

. Escherichia coli adapts to tetracycline resistance plasmid (pBR322) by mutating endogenous potassium transport: in silico hypothesis testing[J]. FEMS Microbiology Ecology, 2013, 83(3): 622-631.

[58]

MACHUCA

, BRIALES

, DÍAZ-DE-ALBA

, MARTÍNEZ-MARTÍNEZ

, PASCUAL

, RODRÍGUEZ-MARTÍNEZ

. Effect of the efflux pump QepA2 combined with chromosomally mediated mechanisms on quinolone resistance and bacterial fitness in Escherichia coli [J]. Journal of Antimicrobial Chemotherapy, 2015, 70(9): 2524-2527.

[59]

WANG

, GUO

, ZHI

, YANG

, ZHAO

, CHEN

, ZENG

, LV

, ZENG

, LIU

. Impact of plasmid-borne oqxAB on the development of fluoroquinolone resistance and bacterial fitness in Escherichia coli [J]. Journal of Antimicrobial Chemotherapy, 2017, 72(5): 1293-1302.

[60]

BUDDLE

, THOMPSON

, WILLIAMS

, WRIGHT

RCT

, DURHAM

, TURNER

, CHAUDHURI

, BROCKHURST

, FAGAN

. Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits[J]. PLoS Biology, 2024, 22(8): e3002741.

[61]

LIOY

, GOUSSARD

, GUERINEAU

, YOON

, COURVALIN

, GALIMAND

, GRILLOT-COURVALIN

. Aminoglycoside resistance 16S rRNA methyltransferases block endogenous methylation, affect translation efficiency and fitness of the host[J]. RNA, 2014, 20(3): 382-391.

[62]

LaMARRE

, LOCKE

, SHAW

, MANKIN

. Low fitness cost of the multidrug resistance gene cfr [J]. Antimicrobial Agents and Chemotherapy, 2011, 55(8): 3714-3719.

[63]

NANG

, MORRIS

, McDONALD

, HAN

, WANG

, STRUGNELL

, VELKOV

, LI

. Fitness cost of mcr-1-mediated polymyxin resistance in Klebsiella pneumoniae [J]. Journal of Antimicrobial Chemotherapy, 2018, 73(6): 1604-1610.

[64]

, LIU

, YUE

, BERGEN

, WU

, LI

, LIU

. Overexpression of mcr-1 disrupts cell envelope synthesis and causes the dysregulation of carbon metabolism, redox balance and nucleic acids[J]. International Journal of Antimicrobial Agents, 2022, 60(3): 106643.

[65]

PHAN

, FERENCI

. The fitness costs and trade-off shapes associated with the exclusion of nine antibiotics by OmpF porin channels[J]. The ISME Journal, 2017, 11(6): 1472-1482.

[66]

MELNIKOV

, STEVENS

, FU

, KWOK

, ZHANG

, SHEN

, SABINA

, LEE

, SÖLL

. Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations[J]. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117(30): 17924-17931.

[67]

RASOULY

, SHAMOVSKY

, EPSHTEIN

, TAM K, VASILYEV

, HAO

, QUARTA

, PANI

, LI

, VALLIN

, SHAMOVSKY

, KRISHNAMURTHY

, SHTILERMAN

, VANTINE

, TORRES

, NUDLER

. Analysing the fitness cost of antibiotic resistance to identify targets for combination antimicrobials[J]. Nature Microbiology, 2021, 6(11): 1410-1423.

[68]

ZHANG

, XIAO

, WANG

, ZHAO

, CHEN

, JI

, GU

, WANG

, LIU

. DNA polymerase IV dinB favors the adaptive fitness of mcr-carrying bacteria through a negative feedback regulatory mechanism[J]. Advanced Science, 2025, 12(12): 2411994.

[69]

ROEMHILD

, ANDERSSON

. Mechanisms and therapeutic potential of collateral sensitivity to antibiotics[J]. PLoS Pathogens, 2021, 17(1): e1009172.

[70]

杨浩. 喹诺酮耐药的铜绿假单胞菌对氨基糖苷类抗生素的附带敏感性机制研究[D]. 兰州: 兰州大学, 2025.

YANG

. Study on the mechanism of collateral sensitivity to aminoglycosides in quinolones-resistant Pseudomonas aeruginosa [D]. Lanzhou: Lanzhou University, 2025 (in Chinese).

[71]

LIU

, PHILLIPS

, WILSON

, FULTON

, TWINE

, WONG

, LININGTON

. Collateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance[J]. Nature Communications, 2023, 14: 1976.

[72]

, WU

, LIU

, LI

, ZHENG

, LI

, ZHANG

, WU

, YU

. Collateral sensitivity to β-lactam antibiotics in evolved apramycin-resistant MRSA[J]. International Journal of Molecular Sciences, 2024, 25(22): 12292.

[73]

ANDERSSON

, HUGHES

. Persistence of antibiotic resistance in bacterial populations[J]. FEMS Microbiology Reviews, 2011, 35(5): 901-911.

[74]

HASAN

, DUTTA

, NGUYEN

ANT

. Revisiting antibiotic resistance: mechanistic foundations to evolutionary outlook[J]. Antibiotics, 2021, 11(1): 40.

[75]

BALBONTÍN

, FRAZÃO

, GORDO

. DNA breaks-mediated fitness cost reveals RNase HI as a new target for selectively eliminating antibiotic-resistant bacteria[J]. Molecular Biology and Evolution, 2021, 38(8): 3220-3234.

[76]

WEN

, CAO

, MI

, HUANG

, LIANG

, WANG

, MA

, ZOU

, LIAO

, LIANG

, WU

. Metabonomics reveals an alleviation of fitness cost in resistant E. coli competing against susceptible E. coli at sub-MIC doxycycline[J]. Journal of Hazardous Materials, 2021, 405: 124215.

[77]

FREIHOFER

, AKBERGENOV

, TEO Y, JUSKEVICIENE

, ANDERSSON

, BÖTTGER

. Nonmutational compensation of the fitness cost of antibiotic resistance in mycobacteria by overexpression of tlyA rRNA methylase[J]. RNA, 2016, 22(12): 1836-1843.

2026年第66卷第2期

PDF下载

246

107

引用本文

BibTeX

文章信息

doi: 10.13343/j.cnki.wsxb.20250668

接收时间：2025-09-01
首发时间：2026-02-05
出版时间：2026-02-04

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2025-09-01
录用日期：2025-11-04

基金

the National Natural Science Foundation of China(32402820)

国家自然科学基金(32402820)

the National Modern Agricultural Industry Technology System(CARS-40)

国家现代农业产业技术体系(CARS-40)

作者信息

^1.华南农业大学动物科学学院，广东广州

^2.山东农业大学动物科技学院，山东泰安

^3.猪禽种业全国重点实验室，广东广州

^4.广东省农业动物基因组学与分子育种重点实验室，广东广州

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/wswxb/CN/10.13343/j.cnki.wsxb.20250668

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2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

Access method of ARGs	Species	ARGs	Resistance mechanism	Characteristics	Fitness cost	Reference
Genetic mutation	Staphylococcus epidermidis	rpoB	Prevent the interaction between rifampicin and the β-subunit of RNA polymerase	The growth rate decreases	RF: <1.0	[27]
Pseudomonas aeruginosa	nfxB	Regulators of multidrug efflux pumps	A large amount of energy is consumed, and the growth rate decreases	Growth curves:P<0.000 1	[28]
gyrA, gyrB	Prevent fluoroquinolones from binding to DNA-modifying subunits of DNA gyrases	No fitness cost	RF: 1.012 (gyrA),1.003 (gyrB)
Mycolicibacterium smegmatis	rv2752c	Encoding a bifunctional RNase J protein with β-lactamase and ribonuclease activities	Decreased transcription efficiency and reduced growth rate	RF: 0.87	[29]
Conjugation	Escherichia coli	bla_CTX-M-14	Enzymes that hydrolyze penicillin and third-generation cephalosporins	Some bacteria lose their conjugative ability	RF: 0.985	[30]
bla_NDM	Enzymes that hydrolyze carbapenem drugs	Decreased virulence and loss of plasmids	RF: 0.813 006	[31]
qnrA, qnrB, qnrS	Protect DNA gyrase and topoisomerase IV from inhibition by quinolone drugs	No fitness cost	RF: 1.030 (qnrA), 1.056 (qnrB), 1.016 (qnrS)	[32]
Salmonella	fosA7	Produce fosfomycin-modifying enzymes	The growth rate is not affected	Growth curves:P=0.844 1	[33]
Transposon	Escherichia coli	sul1,sul2,sul3	Dihydropteroate synthase with low affinity for sulfonamide drugs	The motility is decreased, and the growth rate is reduced (sul3)	S: 0.021>0 (sul1), 0.019>0 (sul2), -0.087<0 (sul3)	[34]
Enterococcus faecium	vanA	The encoded protein alters the synthesis of cell wall peptidoglycan precursors	The growth rate decreases	Growth curves:P<0.001	[35]
Integrator	Escherichia coli	dfrA1-sat2-aadA1	Type II integrons carry gene cassettes with a multi-resistance pattern	The growth rate decreases	S: -0.068<0	[36]
Transduction	Streptococcus suis	mef(A), tet(O)	Efflux pump proteins and ribosome protection proteins	The growth rate increases	Growth curves: the logarithmic phase (2 hours earlier) and the OD₆₉₀peak (3 hours earlier and being 0.25 higher)	[37]
Escherichia coli	bla_CTX-M-55	Enzymes for multiple β-lactam drugs	The growth rate and elevated plasmid loss rate increases (P1)	RF: <1 (No P1), >1 (P1)	[38]

Access method of ARGs

Species

ARGs

Resistance mechanism

Characteristics

Fitness cost

Reference

Genetic mutation

Staphylococcus epidermidis

rpoB

Prevent the interaction between rifampicin and the β-subunit of RNA polymerase

The growth rate decreases

RF: <1.0

[27]

Pseudomonas aeruginosa

nfxB

Regulators of multidrug efflux pumps

A large amount of energy is consumed, and the growth rate decreases

Growth curves:P<0.000 1

[28]

gyrA,

gyrB

Prevent fluoroquinolones from binding to DNA-modifying subunits of DNA gyrases

No fitness cost

RF: 1.012 (gyrA),1.003 (gyrB)

Mycolicibacterium smegmatis

rv2752c

Encoding a bifunctional RNase J protein with β-lactamase and ribonuclease activities

Decreased transcription efficiency and reduced growth rate

RF: 0.87

[29]

Conjugation

Escherichia coli

bla_CTX-M-14

Enzymes that hydrolyze penicillin and third-generation cephalosporins

Some bacteria lose their conjugative ability

RF: 0.985

[30]

bla_NDM

Enzymes that hydrolyze carbapenem drugs

Decreased virulence and loss of plasmids

RF: 0.813 006

[31]

qnrA,

qnrB,

qnrS

Protect DNA gyrase and topoisomerase IV from inhibition by quinolone drugs

No fitness cost

RF: 1.030 (qnrA), 1.056 (qnrB), 1.016 (qnrS)

[32]

Salmonella

fosA7

Produce fosfomycin-modifying enzymes

The growth rate is not affected

Growth curves:P=0.844 1

[33]

Transposon

Escherichia coli

sul1

sul2

sul3

Dihydropteroate synthase with low affinity for sulfonamide drugs

The motility is decreased, and the growth rate is reduced (sul3)

S: 0.021>0 (sul1), 0.019>0 (sul2), -0.087<0 (sul3)

[34]

Enterococcus faecium

vanA

The encoded protein alters the synthesis of cell wall peptidoglycan precursors

The growth rate decreases

Growth curves:P<0.001

[35]

Integrator

Escherichia coli

dfrA1-sat2-aadA1

Type II integrons carry gene cassettes with a multi-resistance pattern

The growth rate decreases

S: -0.068<0

[36]

Transduction

Streptococcus suis

mef(A), tet(O)

Efflux pump proteins and ribosome protection proteins

The growth rate increases

Growth curves: the logarithmic phase (2 hours earlier) and the OD₆₉₀peak (3 hours earlier and being 0.25 higher)

[37]

Escherichia coli

bla_CTX-M-55

Enzymes for multiple β-lactam drugs

The growth rate and elevated plasmid loss rate increases (P1)

RF: <1 (No P1), >1 (P1)

[38]

Vector	Mechanism	Drug	ARGs	Impacted cost pathway	Fitness cost	Reference
Chromosome	Reduced permeability	The extended-spectrum	ompC/F	Impaired nutrient absorption→DNA methylation→DNA binding to proteins	Arrested the growth and replication of bacteria	[40-41]
ompC/F	Decreased expression of csgA/B→impaired curli synthesis	Decreased biofilm formation	[42-43]
Active transport of antibiotics	The extended-spectrum	—	Overexpression of efflux pumps	High energy burden	[15]
mexABOprM, mexCDOprJ	Impact on the rhl QS system→reduced phenazine synthesis; lack of MexA	Decreased virulence	[44]
mexEFOprN	Pumping out PQS precursors→delayed production of PQS signaling molecules	Impaired initiation of PQS function, decreased virulence	[45]
mexEFOprN	H⁺antiport→intracellular H⁺ accumulation	Imbalance of pH homeostasis	[46]
ade group	Downregulated expression of pili and membrane structural proteins	Decreased biofilm formation	[47]
acrABTolC	Promotion of QS signal AHL efflux→binding to membrane receptor SdiA	Promotion of biofilm formation	[48]
Target modification	Aminoglycosides	rrs	A1408G mutation in 16S rRNA gene→no impact on the ON/OFF switching of the A site	No fitness cost	[49]
rrs	A1408C/U mutations in 16S rRNA gene→affect the ON/OFF switching of the A site	Bacterial death	[49]
Rifampicin	ropB	Alteration of the conserved β subunit of RNA polymerase	Decreased transcription efficiency	[6,50]
Plasmid	Inactivation and modification of the drug	β-lactams	bla_KPC-2	Downregulated expression of virulence genes iucA, magA, and rmpA2	Decreased virulence	[51]
bla_FOX-4/8	Overexpression of AmpC enzyme→abnormal peptidoglycan metabolism→interference with cell wall integrity	Decreased virulence	[52]
bla_NDM	Downregulation of locomotion, ATP synthesis, and DNA replication	Decreased motility and replicative capacity	[11]
Tetracyclines	tet(X4)	Downregulated expression of atlR→inability to inhibit the copy number of plasmids	Decreased biofilm formation and virulence	[53]
tetX	Increased ATPase activity and protein synthesis	Increased metabolic burden	[54]
tet(X4)	Encoded the H-NS protein→inhibits tet(X4) expression	No fitness cost	[55]
Active transport of antibiotics	Tetracyclines	tetH	Downregulated expression of fimbrial genes fimA and fimC	Decreased motility	[56]
tetA	Decreased K⁺ uptake efficiency of the Trk system	High energy consumption	[57]
Quinolones	qepA2,oqxAB	gyrA/B mutations that induce the target modification mechanism	Enhanced fitness	[58-59]
Target modification	Glycopeptides	van	Modification of peptidoglycan→defect in sporulation	Decreased infectivity	[60]
Aminoglycosides	armA	Resistant methylation of A1405 in 16S rRNA gene	No fitness cost	[61]
armA	Interference with the endogenous methylation of C1402 by RsmI	Affects ribosome function	[61]
npmA	Resistant methylation of A1408 in 16S rRNA gene	No fitness cost	[61]
npmA	Block the activity of RsmF on C1407	Reduces the accuracy of translation	[61]
Macrolides	cfr	Expression of cfr→resistant methylation of A2503 in 16S rRNA gene	No fitness cost	[62]
cfr	Co-expression of ermB and cfr→dimethylation of A2508	Obstruction of the export tunnel for nascent peptide synthesis	[62]
Polymyxins	mcr-1	Modification of lipid A→obstruction of LPS synthesis	Decreased virulence	[63]
mcr-1	Modification of LPS→downregulation of waa and rml→downregulation of LPS core and O-antigen synthesis	Increased membrane permeability and membrane depolarization	[64]

Vector

Mechanism

Drug

ARGs

Impacted cost pathway

Fitness cost

Reference

Chromosome

Reduced permeability

The extended-spectrum

ompC/F

Impaired nutrient absorption→DNA methylation→DNA binding to proteins

Arrested the growth and replication of bacteria

[40-41]

ompC/F

Decreased expression of csgA/B→impaired curli synthesis

Decreased biofilm formation

[42-43]

Active transport of antibiotics

The extended-spectrum

—

Overexpression of efflux pumps

High energy burden

[15]

mexABOprM,

mexCDOprJ

Impact on the rhl QS system→reduced phenazine synthesis; lack of MexA

Decreased virulence

[44]

mexEFOprN

Pumping out PQS precursors→delayed production of PQS signaling molecules

Impaired initiation of PQS function, decreased virulence

[45]

mexEFOprN

H⁺antiport→intracellular H⁺ accumulation

Imbalance of pH homeostasis

[46]

ade group

Downregulated expression of pili and membrane structural proteins

Decreased biofilm formation

[47]

acrABTolC

Promotion of QS signal AHL efflux→binding to membrane receptor SdiA

Promotion of biofilm formation

[48]

Target modification

Aminoglycosides

rrs

A1408G mutation in 16S rRNA gene→no impact on the ON/OFF switching of the A site

No fitness cost

[49]

rrs

A1408C/U mutations in 16S rRNA gene→affect the ON/OFF switching of the A site

Bacterial death

[49]

Rifampicin

ropB

Alteration of the conserved β subunit of RNA polymerase

Decreased transcription efficiency

[6,50]

Plasmid

Inactivation and modification of the drug

β-lactams

bla_KPC-2

Downregulated expression of virulence genes iucA, magA, and rmpA2

Decreased virulence

[51]

bla_FOX-4/8

Overexpression of AmpC enzyme→abnormal peptidoglycan metabolism→interference with cell wall integrity

Decreased virulence

[52]

bla_NDM

Downregulation of locomotion, ATP synthesis, and DNA replication

Decreased motility and replicative capacity

[11]

Tetracyclines

tet(X4)

Downregulated expression of atlR→inability to inhibit the copy number of plasmids

Decreased biofilm formation and virulence

[53]

tetX

Increased ATPase activity and protein synthesis

Increased metabolic burden

[54]

tet(X4)

Encoded the H-NS protein→inhibits tet(X4) expression

No fitness cost

[55]

Active transport of antibiotics

Tetracyclines

tetH

Downregulated expression of fimbrial genes fimA and fimC

Decreased motility

[56]

tetA

Decreased K⁺ uptake efficiency of the Trk system

High energy consumption

[57]

Quinolones

qepA2

oqxAB

gyrA/B mutations that induce the target modification mechanism

Enhanced fitness

[58-59]

Target modification

Glycopeptides

van

Modification of peptidoglycan→defect in sporulation

Decreased infectivity

[60]

Aminoglycosides

armA

Resistant methylation of A1405 in 16S rRNA gene

No fitness cost

[61]

armA

Interference with the endogenous methylation of C1402 by RsmI

Affects ribosome function

[61]

npmA

Resistant methylation of A1408 in 16S rRNA gene

No fitness cost

[61]

npmA

Block the activity of RsmF on C1407

Reduces the accuracy of translation

[61]

Macrolides

cfr

Expression of cfr→resistant methylation of A2503 in 16S rRNA gene

No fitness cost

[62]

cfr

Co-expression of ermB and cfr→dimethylation of A2508

Obstruction of the export tunnel for nascent peptide synthesis

[62]

Polymyxins

mcr-1

Modification of lipid A→obstruction of LPS synthesis

Decreased virulence

[63]

mcr-1

Modification of LPS→downregulation of waa and rml→downregulation of LPS core and O-antigen synthesis

Increased membrane permeability and membrane depolarization

[64]