铜绿假单胞菌主动外排泵介导的多重抗生素耐药性(英文)  

Efflux-mediated multiple antibiotic resistance in Pseudomonas aeruginosa

作　　者：李显志 

机构地区：[1]美国伯克利加州大学分子细胞生物学系

出　　处：《中国抗生素杂志》2003年第10期577-596,共20页Chinese Journal of Antibiotics

摘　　要：铜绿假单胞菌作为一种机会致病菌 ,对多种临床常用抗生素呈现明显的固有与获得性耐药 ,这种多重耐药性的形成机制在于该菌具有的多种能量依赖性的药物主动外排泵和低通透性外膜屏障协同作用所致。近 10年对铜绿假单胞菌药物外排泵的研究已经颇为深入 ,本文对有关进展予以讨论。在铜绿假单胞菌已报道了 6种属于“耐药—生节—分裂 (RND)”类的药物外排泵系统 ,它们可在天然野生株表达或者由于基因突变而诱导表达 ,从而介导了对β-内酰胺类 (包括β-内酰胺酶抑制剂 )、氨基糖苷类、氟喹诺酮类、大环内酯类及四环素类等的耐药性。这些外排泵中尤其以 Mex AB-Opr M系统的作用底物范围最广 ,在耐药性形成中起主要作用。RND类外排泵系统也普遍存在于其它革兰氏阴性细菌。各外排泵通常由内膜转运体蛋白、内膜融合蛋白及外膜通道蛋白一起形成功能性转运复合体将药物排至胞外。药物外排泵常影响对灭活酶较稳定的抗菌药物。一些新抗菌药物如 L inezolid(Oxa-zolidinoes类 )、Telithromycin(Ketolides类 )及 Tigecycline(Glycyclines类 )也是 Mex AB-Opr M等 RND类外排泵的作用底物 ,故这些药物抗革兰氏阳性细菌的活性较强。铜绿假单胞菌外排泵表达的调控机制多是在转录水平上受局部阻遏物或激活物的作用。Pseudomonas aeruginosa is an opportuni st ic pathogen and displays high-level intrinsic and acquired multiple antimicrobi al resistance. Mechanisms for such resistance are attributed by the interplay between the broad-specific multidrug efflux pumps and the low outer membrane permeability. A total of six multidrug efflux pumps, which belong to the Resista nce-Nodulation-Division (RND) superfamily, have been characterized to date in P.aeruginosa. The RND efflux systems in Gram-negative bacteria are typicall y the three-component pumps, each composed of an inner membrane transporter, an inner membrane-associated periplasmic membrane fusion protein, and an outer me mbrane efflux channel protein. Of these known pumps of P.aeruginosa, the Mex AB-OprM efflux system plays the most important role in drug resistance and show s the broadest substrate ranges that include most conventional classes of antibi otics. Regulation of these pumps is typically linked to local regulators (repres sor or activators), whose mutations or inactivation produce multiple antibio tic-resistant strains as revealed in many clinical isolates. Efflux mechanisms act together with other resistance determinants to further raise resistance leve ls. As such, the efflux pump inhibitors are being sought to combat efflux-media ted drug resistance in order to restore antibacterial activity of antibiotics subject to efflux. Efflux reversal of fluoroquinolones in P.aeruginosa by efflux pump inhibitors has been demonstrated.

关 键 词：铜绿假单胞菌 抗生素多重耐药性 主动外排泵 外排泵抑制剂 

分 类 号：Q93[生物学—微生物学]