鲍曼不动杆菌对替加环素耐药机制研究进展

doi:10.3969/j.issn.1673-8640.2019.07.019

摘要/Abstract

摘要：

鲍曼不动杆菌是一种常见的可引起医院感染的条件致病菌,随着抗菌药物的广泛使用,越来越多的多重耐药鲍曼不动杆菌被分离出来。替加环素是治疗鲍曼不动杆菌感染的最后一道防线,近年来替加环素耐药鲍曼不动杆菌不断出现,而其耐药机制至今尚未被完全阐明。文章对鲍曼不动杆菌主动外排系统及近年新发现的耐药机制,包括修饰酶、细胞膜渗透作用、DNA损伤诱导反应及作用靶点改变等机制作一综述,为细菌耐药及新型抗菌药物研究提供理论依据,为临床控制替加环素耐药鲍曼不动杆菌提供新思路。

关键词: 鲍曼不动杆菌, 替加环素, 耐药机制

Abstract:

Acinetobacter baumannii is a common opportunistic pathogen causing nosocomial infection. With the wide use of antibiotics,more and more multidrug-resistant Acinetobacter baumannii have been isolated. Tigecycline has been known as the last line of defense against Acinetobacter baumannii. In the recent years,tigecycline-resistant Acinetobacter baumannii has appeared,and its drug resistance mechanism has not yet been fully elucidated. This review focuses on the efflux pump system and new drug resistance mechanisms,including modification enzymes,cell membrane osmosis,DNA damage induction response and target changes,which provides a reference for the future researches on bacterial resistance mechanism and new antibiotics and a new idea for the clinical control of tigecycline-resistant Acinetobacter baumannii.

Key words: Acinetobacter baumannii, Tigecycline, Drug resistance mechanism

中图分类号:

R378.99

张心宇, 杜雪飞, 邹桂玲, 姜晓峰. 鲍曼不动杆菌对替加环素耐药机制研究进展[J]. 检验医学, 2019, 34(7): 656-660.

ZHANG Xinyu, DU Xuefei, ZOU Guiling, JIANG Xiaofeng. Research progress of tigecycline resistance mechanism for Acinetobacter baumannii[J]. Laboratory Medicine, 2019, 34(7): 656-660.

参考文献 43

[1]	胡付品,郭燕,朱德妹,等. 2017年CHINET中国细菌耐药性监测[J]. 中国感染与化疗杂志,2018,18(3):241-251.
[2]	胡付品. 2005—2014年CHINET中国细菌耐药性监测网5种重要临床分离菌的耐药性变迁[J]. 中国感染与化疗杂志,2017,17(1):93-99.
[3]	LI J,YANG X,CHEN L,et al.In vitro activity of various antibiotics in combination with tigecycline against Acinetobacter baumannii:a systematic review and meta-analysis[J]. Microb Drug Resist,2017,23(8):982-993.
[4]	GERSON S,NOWAK J,ZANDER E,et al.Diversity of mutations in regulatory genes of resistance-nodulation-cell division efflux pumps in association with tigecycline resistance in Acinetobacter baumannii[J]. J Antimicrob Chemother,2018,73(6):1501-1508.
[5]	LEUS I V,WEEKS J W,BONIFAY V,et al. Substrate specificities and efflux efficiencies of RND efflux pumps of Acinetobacter baumannii[J]. J Bacteriol,2018,200(3):pii:e00049-18.
[6]	PELEG A Y,ADAMS J,PATERSON D L.Tigecycline efflux as a mechanism for nonsusceptibility in Acinetobacter baumannii[J]. Antimicrobial Agents Chemother,2007,51(6):2065-2069.
[7]	COYNE S,ROSENFELD N,LAMBERT T,et al.Overexpression of resistance-nodulation-cell division pump AdeFGH confers multidrug resistance in Acinetobacter baumannii[J]. Antimicrob Agents Chemother,2010,54(10):4389-4393.
[8]	ESWARAN J,KORONAKIS E,HIGGINS M K,et al.Three's company:component structures bring a closer view of tripartite drug efflux pumps[J]. Curr Opin Struct Biol,2004,14(6):741-747.
[9]	周翠,徐春泉,陈栎江,等. 多重耐药鲍曼不动杆菌耐药性分析及对替加环素敏感性降低的机制研究[J]. 中国卫生检验杂志,2017,27(7):1050-1052.
[10]	YOON E J,CHABANE Y N,GOUSSARD S,et al. Contribution of resistance-nodulation-cell division efflux systems to antibiotic resistance and biofilm formation in Acinetobacter baumannii[J]. MBio,2015,6(2):pii:e00309-15.
[11]	DENG M,ZHU M H,LI J J,et al.Molecular epidemiology and mechanisms of tigecycline resistance in clinical isolates of Acinetobacter baumannii from a Chinese university hospital[J]. Antimicrob Agents Chemother,2014,58(1):297-303.
[12]	RUMBO C,GATO E,LÓPEZ M,et al. Contribution of efflux pumps,porins,and β-lactamases to multidrug resistance in clinical isolates of Acinetobacter baumannii[J]. Antimicrob Agents Chemother,2013,57(11):5247-5257.
[13]	COYNE S,GUIGON G,COURVALIN P,et al.Screening and quantification of the expression of antibiotic resistance genes in Acinetobacter baumannii with a microarray[J]. Antimicrob Agents Chemother,2010,54(1):333-340.
[14]	AMIN I M,RICHMOND G E,SEN P,et al.A method for generating marker-less gene deletions in multidrug-resistant Acinetobacter baumannii[J]. BMC Microbiol,2013,13:158.
[15]	吕月贤. 亚抑菌浓度替加环素对鲍曼不动杆菌生物膜影响的研究[D]. 长春:吉林大学,2017.
[16]	HE S,HE H,CHEN Y,et al.In vitro and in vivo analysis of antimicrobial agents alone and in combination against multi-drug resistant Acinetobacter baumannii[J]. Front Microbiol,2015,6:507.
[17]	INABA M,MATSUDA N,BANNO H,et al.In vitro reduction of antibacterial activity of tigecycline against multidrug-resistant Acinetobacter baumannii with host stress hormone norepinephrine[J]. Int J Antimicrob Agents,2016,48(6):680-689.
[18]	ROSENFELD N,BOUCHIER C,COURVALIN P,et al.Expression of the resistance-nodulation-cell division pump AdeIJK in Acinetobacter baumannii is regulated by AdeN,a TetR-type regulator[J]. Antimicrob Agents Chemother,2012,56(5):2504-2510.
[19]	DAMIER-PIOLLE L,MAGNET S,BRÉMONT S,et al. AdeIJK,a resistance-nodulation-cell division pump effluxing multiple antibiotics in Acinetobacter baumannii[J]. Antimicrob Agents Chemother,2008,52(2):557-562.
[20]	ADAMS F G,STROEHER U H,HASSAN K A,et al.Resistance to pentamidine is mediated by AdeAB,regulated by AdeRS,and influenced by growth conditions in Acinetobacter baumannii ATCC 17978[J]. PLoS One,2018,13(5):e0197412.
[21]	SUN J R,CHIANG Y S,SHANG H S,et al.Phenotype microarray analysis of the AdeRS two-component system in Acinetobacter baumannii[J]. Eur J Clin Microbiol Infect Dis,2017,36(12):2343-2353.
[22]	RICHMOND G E,EVANS L P,ANDERSON M J,et al. Erratum for Richmond et al.,The Acinetobacter baumannii two-component system AdeRS regulates genes required for multidrug efflux,biofilm formation, and virulence in a strain-specific manner[J]. MBio,2016,7(3):pii:e00852-16.
[23]	HORNSEY M,ELLINGTON M J,DOUMITH M,et al.AdeABC-mediated efflux and tigecycline MICs for epidemic clones of Acinetobacter baumannii[J]. J Antimicrob Chemother,2010,65(8):1589-1593.
[24]	COYNE S,GUIGON G,COURVALIN P,et al.Screening and quantification of the expression of antibiotic resistance genes in Acinetobacter baumannii with a microarray[J]. Antimicrob Agents Chemother,2010,54(1):333-340.
[25]	HASSAN R,MUKHTAR A,HASANIN A,et al.Role of insertion sequence Aba-1 and AdeS in reduced tigecycline susceptibility in MDR-Acinetobacter baumannii clinical isolates from Cairo,Egypt[J]. J Chemother,2018,30(2):89-94.
[26]	CHANG T Y,HUANG B J,SUN J R,et al.AdeR protein regulates adeABC expression by binding to a direct-repeat motif in the intercistronic spacer[J]. Microbiol Res,2016,183:60-67.
[27]	LIN M F,LIN Y Y,YEH H W,et al.Role of the BaeSR two-component system in the regulation of Acinetobacter baumannii adeAB genes and its correlation with tigecycline susceptibility[J]. BMC Microbiol,2014,14:119.
[28]	LIN M F,LIN Y Y,LAN C Y.The role of the two-component system BaeSR in disposing chemicals through regulating transporter systems in Acinetobacter baumannii[J]. PLoS One,2015,10(7):e0132843.
[29]	MOORE I F,HUGHES D W,WRIGHT G D.Tigecycline is modified by the flavin-dependent monooxygenase TetX[J]. Biochemistry,2005,44(35):11829-11835.
[30]	BARTHA N A,SOKI J,URBÁN E,et al. Investigation of the prevalence of tetQ,tetX and tetX1 genes in Bacteroides strains with elevated tigecycline minimum inhibitory concentrations[J]. Int J Antimicrob Agents,2011,38(6):522-525.
[31]	陈琼. 鲍曼不动杆菌替加环素耐药机制研究[D]. 杭州:浙江大学,2015.
[32]	LI X,QUAN J,YANG Y,et al.Abrp,a new gene,confers reduced susceptibility to tetracycline,glycylcine,chloramphenicol and fosfomycin classes in Acinetobacter baumannii[J]. Eur J Clin Microbiol Infect Dis,2016,35(8):1371-1375.
[33]	LI X,LIU L,JI J,et al.Tigecycline resistance in Acinetobacter baumannii mediated by frameshift mutation in plsC,encoding 1-acyl-sn-glycerol-3-phosphate acyltransferase[J]. Eur J Clin Microbiol Infect Dis,2015,34(3):625-631.
[34]	DAVIES B W,KOHANSKI M A,SIMMONS L A,et al.Hydroxyurea induces hydroxyl radical-mediated cell death in Escherichia coli[J]. Mol Cell,2009,36(5):845-860.
[35]	ARANDA J,LÓPEZ M,LEIVA E,et al. Role of Acinetobacter baumannii UmuD homologs in antibiotic resistance acquired through DNA damage-induced mutagenesis[J]. Antimicrob Agents Chemother,2014,58(3):1771-1773.
[36]	AJIBOYE T O,SKIEBE E,WILHARM G.Contributions of RecA and RecBCD DNA repair pathways to the oxidative stress response and sensitivity of Acinetobacter baumannii to antibiotics[J]. Int J Antimicrob Agents,2018,52(5):629-636.
[37]	BEABOUT K,HAMMERSTROM T G,PEREZ A M,et al.The ribosomal S10 protein is a general target for decreased tigecycline susceptibility[J]. Antimicrob Agents Chemother,2015,59(9):5561-5566.
[38]	HAMMERSTROM T G,BEABOUT K,CLEMENTS T P,et al.Acinetobacter baumannii repeatedly evolves a hypermutator phenotype in response to tigecycline that effectively surveys evolutionary trajectories to resistance[J]. PLoS One,2015,10(10):e140489.
[39]	HE F,SHI Q,FU Y,et al.Tigecycline resistance caused by rpsJ evolution in a 59-year-old male patient infected with KPC-producing Klebsiella pneumoniae during tigecycline treatment[J]. Infect Genet Evol,2018,66:188-191.
[40]	CHEN Q,LI X,ZHOU H,et al.Decreased susceptibility to tigecycline in Acinetobacter baumannii mediated by a mutation in trm encoding SAM-dependent methyltransferase[J]. J Antimicrob Chemother,2014,69(1):72-76.
[41]	TREBOSC V,GARTENMANN S,ROYET K,et al.A novel genome-editing platform for drug-resistant Acinetobacter baumannii reveals an AdeR-unrelated tigecycline resistance mechanism[J]. Antimicrob Agents Chemother,2016,60(12):7263-7271.
[42]	MORI I,SAVI M,TOMI T I,et al.rRNA methyltransferases and their role in resistance to antibiotics[J]. J Med Biochem,2010,29:165-174.
[43]	何秀娟,李荷楠,王启,等. 替加环素不敏感鲍曼不动杆菌的分子流行病学及耐药机制[J]. 生物工程学报,2018,34(8):1218-1225.