细菌耐药：生化机制与应对策略

doi:10.13560/j.cnki.biotech.bull.1985.2022-0759

摘要/Abstract

摘要：

抗生素的过度使用以及滥用加速了细菌耐药性的产生及蔓延。细菌耐药性俨然已成为导致人类死亡的第三大原因,严重威胁了全球公共健康。因此,当下亟需加强细菌耐药的机制研究,并探索应对耐药性的新型防控策略。针对几类重要耐药细菌,本文就细菌耐药的主要生化机制：药物渗透障碍、药物作用靶位改变、药物失活以及主动外排进行了总结;并对其防控策略：抗菌肽疗法、免疫疗法、噬菌体疗法、抗菌光动力疗法、益生菌疗法、抗菌纳米颗粒技术、反义寡核苷酸和基因编辑技术、宿主导向疗法等进行了归纳。该综述致力于为细菌耐药性进行科普,并为耐药性的相关研究提供参考。

关键词: 抗生素, 细菌耐药性, 生化机制, 应对细菌耐药性策略

Abstract:

The improper use of antibiotics promotes the emergence and global dissemination of antimicrobial resistance（AMR）. AMR is listed as the 3^rd cause leading to human death,seriously threatening public health and food security. Therefore,it is urgently demanded to enhance the studies on AMR mechanisms,and pursue novel prevention and control strategies against AMR. This review summaries major AMR biochemical mechanisms,including drug uptake limitation,drug target modification,drug inactivation,and active drug efflux. Then the review outlines its prevention and control approaches such as antimicrobial peptide therapy,immunotherapy,phage therapy,antimicrobial photodynamic therapy,probiotic therapy,antimicrobial nanoparticle technology,antisense oligonucleotide and gene editing technology,host-directed therapy,etc. This review aims to popularize the science of bacterial drug resistance and provide a reference for relevant studies on drug resistance.

Key words: antibiotics, antimicrobial resistance（AMR）, biochemical mechanisms, approaches against AMR

刘成程, 胡小芳, 冯友军. 细菌耐药：生化机制与应对策略[J]. 生物技术通报, 2022, 38(9): 4-16.

LIU Cheng-cheng, HU Xiao-fang, FENG You-jun. Antimicrobial Resistance：Biochemical Mechanisms and Countermeasures[J]. Biotechnology Bulletin, 2022, 38(9): 4-16.

图/表 8

参考文献 77

[1]	Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics:the WHO priority list of antibiotic-resistant bacteria and tuberculosis[J]. Lancet Infect Dis, 2018, 18(3):318-327. doi: S1473-3099(17)30753-3 pmid: 29276051
[2]	Collaborators AR. Global burden of bacterial antimicrobial resistance in 2019:a systematic analysis[J]. Lancet, 2022, 399(10325):629-655. doi: 10.1016/S0140-6736(21)02724-0 URL
[3]	O'Neill J. Review on antimicrobial resistance:tackling drug-resistant infections globally:final report and recommendations[M]. London: Welcome Trust, 2016.
[4]	全国细菌耐药监测网. 2020年全国细菌耐药监测报告[J]. 中华检验医学杂志, 2022(2):122-136.
	China Antimicrobial Resistance Surveillance System. 2020 National antimicrobial resistance surveillance report[J]. Chin J Infect Control, 2022(2):122-136.
[5]	Frieden T. Antibiotic resistance threats in the United States, 2013[M]. Atlanta: Centers for Disease Control and Prevention(U. S.), 2013.
[6]	孙双勇, 王蒙蒙, 李丽, 等. 抗生素耐药与抗生素新药开发的研究进展[J]. 现代药物与临床, 2022, 37(2):221-229.
	Sun SY, Wang MM, Li L, et al. Research progress on antibiotic resistance and new antibiotics development[J]. Drugs ＆ Clin, 2022, 37(2):221-229.
[7]	Reygaert WC. An overview of the antimicrobial resistance mechanisms of bacteria[J]. AIMS Microbiol, 2018, 4(3):482-501. doi: 10.3934/microbiol.2018.3.482 pmid: 31294229
[8]	Munita JM, Arias CA. Mechanisms of antibiotic resistance[J]. Microbiol Spectr, 2016, 4(2):4.2.15. https://doi.org/10.1128/microbiolspecVMBF-0016-2015.
[9]	Kumar A, Schweizer HP. Bacterial resistance to antibiotics:active efflux and reduced uptake[J]. Adv Drug Deliv Rev, 2005, 57(10):1486-1513. doi: 10.1016/j.addr.2005.04.004 URL
[10]	Balabanian G, Rose M, Manning N, et al. Effect of porins and bla_KPC expression on activity of imipenem with relebactam in Klebsiella pneumoniae:can antibiotic combinations overcome resistance?[J]. Microb Drug Resist, 2018, 24(7):877-881. doi: 10.1089/mdr.2018.0065 pmid: 29782237
[11]	Vergalli J, Bodrenko IV, Masi M, et al. Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria[J]. Nat Rev Microbiol, 2020, 18(3):164-176. doi: 10.1038/s41579-019-0294-2 pmid: 31792365
[12]	Shen JL, Pan YP, Fang YP. Role of the outer membrane protein OprD2 in carbapenem-resistance mechanisms of Pseudomonas aeruginosa[J]. PLoS One, 2015, 10(10):e0139995. doi: 10.1371/journal.pone.0139995 URL
[13]	Hall CW, Mah TF. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria[J]. FEMS Microbiol Rev, 2017, 41(3):276-301. doi: 10.1093/femsre/fux010 pmid: 28369412
[14]	Naparstek L, Carmeli Y, Navon-Venezia S, et al. Biofilm formation and susceptibility to gentamicin and colistin of extremely drug-resistant KPC-producing Klebsiella pneumoniae[J]. J Antimicrob Chemother, 2014, 69(4):1027-1034. doi: 10.1093/jac/dkt487 pmid: 24408988
[15]	Nishimura S, Tsurumoto T, Yonekura A, et al. Antimicrobial susceptibility of Staphylococcus aureus and Staphylococcus epidermidis biofilms isolated from infected total hip arthroplasty cases[J]. J Orthop Sci, 2006, 11(1):46-50. pmid: 16437348
[16]	韩飞, 袁子添, 梁新丽, 等. 细菌生物被膜耐药机制及天然药物干预的研究进展[J]. 中国中药杂志, 2021, 46(14):3560-3565.
	Han F, Yuan ZT, Liang XL, et al. Research advances in drug resistance mechanisms of bacterial biofilm and natural drug intervention[J]. China J Chin Mater Med, 2021, 46(14):3560-3565.
[17]	李超, 王明琼, 赵永攀, 等. 喹诺酮类药物耐药机制研究进展[J]. 动物医学进展, 2022, 43(2):112-115.
	Li C, Wang MQ, Zhao YP, et al. Advance in resistance mechanism of quinolones[J]. Prog Vet Med, 2022, 43(2):112-115.
[18]	Redgrave LS, Sutton SB, et al. Fluoroquinolone resistance:mechanisms, impact on bacteria, and role in evolutionary success[J]. Trends Microbiol, 2014, 22(8):438-445. doi: 10.1016/j.tim.2014.04.007 pmid: 24842194
[19]	Bush K, Bradford PA. β-lactams and β-lactamase inhibitors:an overview[J]. Cold Spring Harb Perspect Med, 2016, 6(8):a025247. doi: 10.1101/cshperspect.a025247 URL
[20]	Peterson E, Kaur P. Antibiotic resistance mechanisms in bacteria:relationships between resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogens[J]. Front Microbiol, 2018, 9:2928. doi: 10.3389/fmicb.2018.02928 URL
[21]	Cox G, Wright GD. Intrinsic antibiotic resistance:mechanisms, origins, challenges and solutions[J]. Int J Med Microbiol, 2013, 303(6/7):287-292. doi: 10.1016/j.ijmm.2013.02.009 URL
	蔡家安, 蒋露芳, 姜庆五. 多黏菌素耐药及其机制的研究进展[J]. 上海预防医学, 2022, 34(3):283-287.
	Cai JA, Jiang LF, Jiang QW. Progress in the study of polymyxin resistance and its mechanism[J]. Shanghai J Prev Med, 2022, 34(3):283-287.
[23]	Girardello R, Visconde M, Cayô R, et al. Diversity of polymyxin resistance mechanisms among Acinetobacter baumannii clinical isolates[J]. Diagn Microbiol Infect Dis, 2017, 87(1):37-44. doi: 10.1016/j.diagmicrobio.2016.10.011 URL
[24]	Liu YY, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China:a microbiological and molecular biological study[J]. Lancet Infect Dis, 2016, 16(2):161-168. doi: 10.1016/S1473-3099(15)00424-7 URL
[25]	Sun J, Zhang HM, et al. Towards understanding MCR-like colistin resistance[J]. Trends Microbiol, 2018, 26(9):794-808. doi: S0966-842X(18)30042-8 pmid: 29525421
[26]	王秀娜, 张会敏, 孙坚, 等. 多黏菌素耐药MCR-1:公共卫生领域的新挑战[J]. 科学通报, 2017, 62(10):1018-1029.
	Wang XN, Zhang HM, Sun J, et al. The MCR-1 colistin resistance:a new challenge to global public health[J]. Chin Sci Bull, 2017, 62(10):1018-1029. doi: 10.1360/N972016-01084 URL
[27]	Tang B, Chang J, Zhang L, et al. Carriage of distinct mcr-1-harboring plasmids by unusual serotypes of Salmonella[J]. Adv Biosyst, 2020, 4(3):e1900219.
[28]	Feng YJ. Transferability of MCR-1/2 polymyxin resistance:complex dissemination and genetic mechanism[J]. ACS Infect Dis, 2018, 4(3):291-300. doi: 10.1021/acsinfecdis.7b00201 URL
[29]	Zhang HM, Srinivas S, et al. Genetic and biochemical mechanisms for bacterial lipid A modifiers associated with polymyxin resistance[J]. Trends Biochem Sci, 2019, 44(11):973-988. doi: S0968-0004(19)30135-5 pmid: 31279652
[30]	Wang CC, Feng Y, Liu LN, et al. Identification of novel mobile colistin resistance gene mcr-10[J]. Emerg Microbes Infect, 2020, 9(1):508-516. doi: 10.1080/22221751.2020.1732231 URL
[31]	Wang YN, Liu F, Hu YF, et al. Detection of mobile colistin resistance gene mcr-9 in carbapenem-resistant Klebsiella pneumoniae strains of human origin in Europe[J]. J Infect, 2020, 80(5):578-606.
[32]	Tang B, Yang H, Jia X, et al. Coexistence and characterization of Tet(X5)and NDM-3 in the MDR-Acinetobacter Indicus of duck origin[J]. Microb Pathog, 2021, 150:104697. doi: 10.1016/j.micpath.2020.104697 URL
[33]	Umar Z, Chen QW, Tang B, et al. The poultry pathogen Riemerella anatipestifer appears as a reservoir for Tet(X)tigecycline resistance[J]. Environ Microbiol, 2021, 23(12):7465-7482. doi: 10.1111/1462-2920.15632 URL
[34]	Kim DW, Thawng CN, Lee K, et al. A novel sulfonamide resistance mechanism by two-component flavin-dependent monooxygenase system in sulfonamide-degrading actinobacteria[J]. Environ Int, 2019, 127:206-215. doi: 10.1016/j.envint.2019.03.046 URL
[35]	韦立志, 李发娟, 何乃奥. 大环内酯类抗生素作用机制及耐药机制和应用的研究进展[J]. 临床合理用药杂志, 2019, 12(15):175-178.
	Wei LZ, Li FJ, He NA. Research progress on the mechanism of action, drug resistance and application of macrolide antibiotics[J]. Chin J Clin Ration Drug Use, 2019, 12(15):175-178.
[36]	宗辉, 孙钰芳, 陈思敏, 等. β-内酰胺酶抑制剂复方制剂研究进展[J]. 中国新药杂志, 2022, 31(4):343-351.
	Zong H, Sun YF, et al. An update on the combinations with β-lactamase inhibitors[J]. Chin J New Drugs, 2022, 31(4):343-351.
[37]	Li P, Liang QQ, Liu WG, et al. Convergence of carbapenem resistance and hypervirulence in a highly-transmissible ST11 clone of K. pneumoniae:an epidemiological, genomic and functional study[J]. Virulence, 2021, 12(1):377-388. doi: 10.1080/21505594.2020.1867468 URL
[38]	Bajaj P, Singh NS, Virdi JS. Escherichia coli β-lactamases:what really matters[J]. Front Microbiol, 2016, 7:417.
[39]	Friedman ND, Temkin E, Carmeli Y. The negative impact of antibiotic resistance[J]. Clin Microbiol Infect, 2016, 22(5):416-422. doi: 10.1016/j.cmi.2015.12.002 URL
[40]	Walsh TR, Weeks J, Livermore DM, et al. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health:an environmental point prevalence study[J]. Lancet Infect Dis, 2011, 11(5):355-362. doi: 10.1016/S1473-3099(11)70059-7 URL
[41]	Grossman TH. Tetracycline antibiotics and resistance[J]. Cold Spring Harb Perspect Med, 2016, 6(4):a025387. doi: 10.1101/cshperspect.a025387 URL
[42]	豆清娅, 邹明祥, 李军. AdeABC外排泵系统与鲍曼不动杆菌对碳青霉烯类药物耐药的关系[J]. 中南大学学报(医学版), 2017, 42(4):426-433.
	Dou QY, Zou MX, Li J, et al. AdeABC efflux pump and resistance of Acinetobacter baumannii against carbapenem[J]. J Cent South Univ(Med Sci), 2017, 42(4):426-433.
[43]	Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance[J]. Nature, 2015, 517(7535):455-459. doi: 10.1038/nature14098 URL
[44]	许丽君, 张瑞, 董春明. 抗菌肽LL-37研究进展[J]. 军事医学, 2022, 46(7):551-557.
	Xu LJ, Zhang R, Dong CM. Research progress in antibacterial peptide LL-37[J]. Mil Med Sci, 2022, 46(7):551-557.
[45]	陈旋, 李莉蓉. 抗菌肽P7抑制大肠杆菌的非膜作用机制[J]. 微生物学报, 2016, 56(11):1737-1745.
	Chen X, Li LR. Non-membrane mechanisms of antimicrobial peptide P7 against Escherichia coli[J]. Acta Microbiol Sin, 2016, 56(11):1737-1745.
[46]	顾江, 曾浩, 邹全明. 创新细菌疫苗的研究进展及挑战[J]. 中国生物制品学杂志, 2021, 34(9):1017-1022.
	Gu J, Zeng H, Zou QM. Advances and challenges in research on innovative bacterial vaccines[J]. Chin J Biol, 2021, 34(9):1017-1022.
[47]	邹全明, 曾浩. 超级细菌疫苗研究的挑战与策略[J]. 第三军医大学学报, 2019, 41(19):1823-1825, 1827.
	Zou QM, Zeng H. Development of vaccines against superbugs:challenges and strategies[J]. J Third Mil Med Univ, 2019, 41(19):1823-1825, 1827.
[48]	熊雪, 陈涛, 刘亚君, 等. 噬菌体抗感染及临床应用进展[J]. 中华危重病急救医学, 2021(4):497-499. pmid: 34053499
	Xiong X, Chen T, Liu YJ, et al. Anti-infection effect of phage and its clinical application[J]. Chin Crit Care Med, 2021(4):497-499. doi: 10.3760/cma.j.cn121430-20201118-00717 pmid: 34053499
[49]	高雅, 王兆飞, 严亚贤. 噬菌体治疗肺炎克雷伯菌感染的研究进展[J]. 微生物学通报, 2021, 48(9):3271-3280.
	Gao Y, Wang ZF, Yan YX. Advances in the treatment of Klebsiella pneumoniae infection with bacteriophage therapy[J]. Microbiol China, 2021, 48(9):3271-3280.
[50]	Tkhilaishvili T, Winkler T, Müller M, et al. Bacteriophages as adjuvant to antibiotics for the treatment of periprosthetic joint infection caused by multidrug-resistant Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother, 2019, 64(1):e00924-e00919.
[51]	Tkhilaishvili T, Merabishvili M, et al. Successful case of adjunctive intravenous bacteriophage therapy to treat left ventricular assist device infection[J]. J Infect, 2021, 83(3):e1-e3.
[52]	李莉莎, 李建辉, 何斌, 等. 噬菌体治疗泛耐药肺炎克雷伯菌肺部感染的临床应用及效果初探[J]. 上海交通大学学报:医学版, 2021, 41(9):1272-1276.
	Li LS, Li JH, He B, et al. Clinical application and effect of phage on the treatment of pulmonary infection by pan-drug resistant Klebsiella pneumoniae[J]. J Shanghai Jiao Tong Univ Med Sci, 2021, 41(9):1272-1276.
[53]	Hamblin MR, Hasan T. Photodynamic therapy:a new antimicrobial approach to infectious disease?[J]. Photochem Photobiol Sci, 2004, 3(5):436-450. doi: 10.1039/b311900a URL
[54]	St Denis TG, Dai TH, Izikson L, et al. All You need is light:antimicrobial photoinactivation as an evolving and emerging discovery strategy against infectious disease[J]. Virulence, 2011, 2(6):509-520. doi: 10.4161/viru.2.6.17889 URL
[55]	Liu CC, Zhou YL, Wang L, et al. Photodynamic inactivation of Klebsiella pneumoniae biofilms and planktonic cells by 5-aminolevulinic acid and 5-aminolevulinic acid methyl ester[J]. Lasers Med Sci, 2016, 31(3):557-565. doi: 10.1007/s10103-016-1891-1 URL
[56]	Liu CC, Hu M, Ma DD, et al. Photodynamic inactivation of antibiotic-resistant bacteria and biofilms by hematoporphyrin monomethyl ether[J]. Lasers Med Sci, 2016, 31(2):297-304. doi: 10.1007/s10103-015-1859-6 URL
[57]	Kashef N, Hamblin MR. Can microbial cells develop resistance to oxidative stress in antimicrobial photodynamic inactivation?[J]. Drug Resist Updat, 2017, 31:31-42. doi: 10.1016/j.drup.2017.07.003 URL
[58]	Zhang MM, Cui ZX, Wang YL, et al. Effects of sub-lethal antimicrobial photodynamic therapy mediated by haematoporphyrin monomethyl ether on polymyxin-resistant Escherichia coli clinical isolate[J]. Photodiagnosis Photodyn Ther, 2021, 36:102516. doi: 10.1016/j.pdpdt.2021.102516 URL
[59]	Hill C, Guarner F, Reid G, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic[J]. Nat Rev Gastroenterol Hepatol, 2014, 11(8):506-514. doi: 10.1038/nrgastro.2014.66 URL
[60]	滕坤玲, 钟瑾. 益生菌产生的细菌素及其功能机制[J]. 微生物学报, 2022, 62(3):858-868.
	Teng KL, Zhong J. Functions and mechanisms of bacteriocins produced by probiotics[J]. Acta Microbiol Sin, 2022, 62(3):858-868.
[61]	Takagi A, Yanagi H, Ozawa H, et al. Effects of Lactobacillus gasseri OLL2716 on Helicobacter pylori-associated dyspepsia:a multicenter randomized double-blind controlled trial[J]. Gastroenterol Res Pract, 2016, 2016:7490452.
[62]	Hwang IY, Koh E, Wong A, et al. Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models[J]. Nat Commun, 2017, 8:15028. doi: 10.1038/ncomms15028 URL
[63]	黄小全. 纳米硒、纳米钌对耐药细菌的抗菌活性及其机制研究[D]. 广州: 暨南大学, 2016.
	Huang XQ. Antibacterial activities and mechanisms of nano selenium and nano ruthenium on drug resistant bacteria[D]. Guangzhou: Jinan University, 2016.
[64]	Kedziora A, Korzekwa K, Strek W, et al. Silver nanoforms as a therapeutic agent for killing Escherichia coli and certain ESKAPE pathogens[J]. Curr Microbiol, 2016, 73(1):139-147. doi: 10.1007/s00284-016-1034-8 pmid: 27086305
[65]	Murugaiyan J, Kumar PA, Rao GS, et al. Progress in alternative strategies to combat antimicrobial resistance:focus on antibiotics[J]. Antibiotics(Basel), 2022, 11(2):200.
[66]	Good L, Stach JEM. Synthetic RNA silencing in bacteria - antimicrobial discovery and resistance breaking[J]. Front Microbiol, 2011, 2:185. doi: 10.3389/fmicb.2011.00185 pmid: 21941522
[67]	达飞. 以agrA为靶点的反义锁核酸抗MRSA活性研究[D]. 西安: 第四军医大学, 2013.
	Da F. Targeting agrA to combat methicillin-resistant Staphylococcus aureus by antisense locked nucleic acid[D]. Xi'an: The Fourth Military Medical University, 2013.
[68]	Kim JS, Cho DH, Park M, et al. CRISPR/Cas9-mediated re-sensitization of antibiotic-resistant Escherichia coli harboring extended-spectrum β-lactamases[J]. J Microbiol Biotechnol, 2016, 26(2):394-401. doi: 10.4014/jmb.1508.08080 URL
[69]	Citorik RJ, Mimee M, Lu TK. Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases[J]. Nat Biotechnol, 2014, 32(11):1141-1145. doi: 10.1038/nbt.3011 pmid: 25240928
[70]	Bikard D, Euler CW, Jiang WY, et al. Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials[J]. Nat Biotechnol, 2014, 32(11):1146-1150. doi: 10.1038/nbt.3043 pmid: 25282355
[71]	Gholizadeh P, Köse Ş, Dao S, et al. How CRISPR-cas system could be used to combat antimicrobial resistance[J]. Infect Drug Resist, 2020, 13:1111-1121. doi: 10.2147/IDR.S247271 pmid: 32368102
[72]	Mohan M, Bhattacharya D. Host-directed therapy:a new arsenal to come[J]. Comb Chem High Throughput Screen, 2021, 24(1):59-70. doi: 10.2174/1386207323999200728115857 URL
[73]	虞翔, 吴叶鉴, 冀磊. 宿主导向的抗菌和抗病毒治疗[J]. 国外医药:抗生素分册, 2018, 39(6):507-521.
	Yu X, Wu YJ, Ji L. Host-directed therapy against bacteria and viruses[J]. World Notes Antibiot, 2018, 39(6):507-521.
[74]	刘畅, 沈瀚. 后抗生素时代的辅助抗菌策略研究进展[J]. 生物技术通讯, 2020, 31(6):736-742.
	Liu C, Shen H. Advances of assisted antimicrobial strategies in the post-antibiotic era[J]. Lett Biotechnol, 2020, 31(6):736-742.
[75]	Sikdar R, Elias M. Quorum quenching enzymes and their effects on virulence, biofilm, and microbiomes:a review of recent advances[J]. Expert Rev Anti Infect Ther, 2020, 18(12):1221-1233. doi: 10.1080/14787210.2020.1794815 URL
[76]	曾莉莉, 史道华, 牛培广. 铜绿假单胞菌群体感应系统及其抑制剂的研究进展[J]. 中国抗生素杂志, 2014, 39(9):701-705, 714.
	Zeng LL, Shi DH, Niu PG. Research progress in quorum sensing system and its inhibitors of Pseudomonas aeruginosa[J]. Chin J Antibiot, 2014, 39(9):701-705, 714.
[77]	傅佳骏, 沈涛, 吴佳, 等. 纳米酶:对抗细菌的新策略[J]. 无机材料学报, 2021, 36(3):257-268. doi: 10.15541/jim20200273
	Fu JJ, Shen T, Wu J, et al. Nanozyme:a new strategy combating bacteria[J]. J Inorg Mater, 2021, 36(3):257-268. doi: 10.15541/jim20200273 URL

抗生素Antibiotics	作用机制Action mechanisms
β-内酰胺类抗生素β-Lactams	抑制细菌细胞壁合成
糖肽类抗生素Glycopeptides	抑制细菌细胞壁合成
脂肽类抗生素Lipopeptides	改变细菌细胞膜通透性
多黏菌素类抗生素Polymyxins	改变细菌细胞膜通透性
氨基糖苷类抗生素Aminoglycosides	抑制细菌蛋白质合成（作用30S 核糖体亚基）
四环素类抗生素Tetracyclines	抑制细菌蛋白质合成（作用30S 核糖体亚基）
氯霉素类抗生素Chloramphenicol	抑制细菌蛋白质合成（作用50S 核糖体亚基）
林可酰胺类抗生素Lincosamides	抑制细菌蛋白质合成（作用50S 核糖体亚基）
大环内酯类抗生素Macrolides	抑制细菌蛋白质合成（作用50S 核糖体亚基）
恶唑烷酮类抗生素Oxazolidinones	抑制细菌蛋白质合成（作用50S 核糖体亚基）
链阳菌素类抗生素Streptogramins	抑制细菌蛋白质合成（作用50S 核糖体亚基）
喹诺酮类抗生素Quinolones	抑制细菌核酸合成
磺胺类抗生素Sulfonamides	抑制细菌代谢途径
甲氧苄啶Trimethoprim	抑制细菌代谢途径

抗生素Antibiotics	作用机制Action mechanisms
β-内酰胺类抗生素β-Lactams	抑制细菌细胞壁合成
糖肽类抗生素Glycopeptides	抑制细菌细胞壁合成
脂肽类抗生素Lipopeptides	改变细菌细胞膜通透性
多黏菌素类抗生素Polymyxins	改变细菌细胞膜通透性
氨基糖苷类抗生素Aminoglycosides	抑制细菌蛋白质合成（作用30S 核糖体亚基）
四环素类抗生素Tetracyclines	抑制细菌蛋白质合成（作用30S 核糖体亚基）
氯霉素类抗生素Chloramphenicol	抑制细菌蛋白质合成（作用50S 核糖体亚基）
林可酰胺类抗生素Lincosamides	抑制细菌蛋白质合成（作用50S 核糖体亚基）
大环内酯类抗生素Macrolides	抑制细菌蛋白质合成（作用50S 核糖体亚基）
恶唑烷酮类抗生素Oxazolidinones	抑制细菌蛋白质合成（作用50S 核糖体亚基）
链阳菌素类抗生素Streptogramins	抑制细菌蛋白质合成（作用50S 核糖体亚基）
喹诺酮类抗生素Quinolones	抑制细菌核酸合成
磺胺类抗生素Sulfonamides	抑制细菌代谢途径
甲氧苄啶Trimethoprim	抑制细菌代谢途径

抗生素 Antibiotics	渗透障碍 Uptake limitation	靶位点改变 Target modification	药物失活 Drug inactivation	主动外排 Active drug efflux
β-内酰胺类抗生素β-Lactams	孔蛋白减少或改变,细胞壁缺失	PBPs改变	β-内酰胺酶产生	RND
糖肽类抗生素Glycopeptides	细胞壁增厚,细胞壁外层缺失	肽聚糖交联减少
氨基糖苷类抗生素Aminoglycosides	细胞壁极性改变	核糖体突变、甲基化	氨基糖苷修饰酶,乙酰化、磷酰化和腺苷酰作用	RND
四环素类抗生素Tetracyclines	孔蛋白减少	核糖体保护作用	抗生素修饰和氧化作用	RND MFS
氯霉素类抗生素Chloramphenicol		核糖体甲基化	乙酰化作用	RND MFS
林可酰胺类抗生素Lincosamides		核糖体甲基化	核苷酸转移酶产生	RND ABC
大环内酯类抗生素Macrolides		核糖体突变、甲基化	糖苷酶、酯酶、磷酸化酶产生	RND MFS ABC
恶唑烷酮类抗生素Oxazolidinones		核糖体甲基化	乙酰基转移酶、水解酶、磷酸转移酶、核苷酸转移酶产生	RND
喹诺酮类抗生素Quinolones		DNA促旋酶修饰,拓扑异构酶Ⅳ结构改变	乙酰化作用,磷酸转移酶产生	MFS MATE
磺胺类抗生素Sulfonamides		DHPS亲和降低	SadA和SadC产生	RND
甲氧苄啶Trimethoprim		DHPS亲和降低		RND
多黏菌素类抗生素Polymyxins	荚膜多糖增加	脂质A修饰改造	降解酶产生	SMR

抗生素 Antibiotics	渗透障碍 Uptake limitation	靶位点改变 Target modification	药物失活 Drug inactivation	主动外排 Active drug efflux
β-内酰胺类抗生素β-Lactams	孔蛋白减少或改变,细胞壁缺失	PBPs改变	β-内酰胺酶产生	RND
糖肽类抗生素Glycopeptides	细胞壁增厚,细胞壁外层缺失	肽聚糖交联减少
氨基糖苷类抗生素Aminoglycosides	细胞壁极性改变	核糖体突变、甲基化	氨基糖苷修饰酶,乙酰化、磷酰化和腺苷酰作用	RND
四环素类抗生素Tetracyclines	孔蛋白减少	核糖体保护作用	抗生素修饰和氧化作用	RND MFS
氯霉素类抗生素Chloramphenicol		核糖体甲基化	乙酰化作用	RND MFS
林可酰胺类抗生素Lincosamides		核糖体甲基化	核苷酸转移酶产生	RND ABC
大环内酯类抗生素Macrolides		核糖体突变、甲基化	糖苷酶、酯酶、磷酸化酶产生	RND MFS ABC
恶唑烷酮类抗生素Oxazolidinones		核糖体甲基化	乙酰基转移酶、水解酶、磷酸转移酶、核苷酸转移酶产生	RND
喹诺酮类抗生素Quinolones		DNA促旋酶修饰,拓扑异构酶Ⅳ结构改变	乙酰化作用,磷酸转移酶产生	MFS MATE
磺胺类抗生素Sulfonamides		DHPS亲和降低	SadA和SadC产生	RND
甲氧苄啶Trimethoprim		DHPS亲和降低		RND
多黏菌素类抗生素Polymyxins	荚膜多糖增加	脂质A修饰改造	降解酶产生	SMR

Ambler分类法 Ambler classification	Bush分类法 Bush classification	代表酶 Representative β-lactamases	底物 Substrates	酶活中心 Active site
A类 Class A	2a	葡萄球菌酶	青霉素类	丝氨酸
	2b	TEM-1,TEM-2,SHV-1	青霉素类和窄谱头孢菌素类
	2be	TEM-10,SHV-2,CTX-M,GES-1	广谱青霉素与头孢菌素类
	2br	TEM-30,SHV-72	青霉素类
	2c	PSE	青霉素类、羧苄青霉素
	2e	CepA	广谱头孢菌素类
	2f	KPC,SEM,NMC-A,GFS-2	青霉素类、头孢菌素类、碳青霉烯类
B类Class B				金属离子
B1	3a	IMP-1,NDM-1,VIM-1	亚胺培南、青霉素类、头孢菌素类
B2	3b	CphA,Sfh-1	碳青霉烯类
B3	3a	L1	头孢菌素类、碳青霉烯类
	3c	FEZ-1	头孢菌素类、碳青霉烯类
C类Class C	1	AmpC	青霉素和头孢菌素类	丝氨酸
D类Class D	2d	OXA-23,OXA-24,OXA-48	青霉素类和氯唑西林以及一些头孢菌素类和碳青霉烯类	丝氨酸