Critical discussion on drug efflux in Mycobacterium tuberculosis.
Critical discussion on drug efflux in Mycobacterium tuberculosis.
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DOI：
10.1093/femsre/fuab050
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发表时间：
2022-02-09
影响因子：
11.3
通讯作者：
Seeger MA
中科院分区：
文献类型：
--
作者：
Remm S;Earp JC;Dick T;Dartois V;Seeger MA
结核分枝杆菌 (Mtb) 可以承受数月的抗生素治疗。结核病研究的一个重要目标是缩短治疗时间以减轻患者负担，提高药物治疗的依从性，从而减缓耐药性的传播。小分子抑制药物外排泵已被认为是攻击持续性结核分枝杆菌并缩短治疗时间的有前途的策略。尽管分枝杆菌药物外排泵已被广泛研究，但机制研究却很少。在这篇批判性综述中，我们通过考虑被注释为药物外排泵、膜能量学、外排抑制剂和细胞壁生物合成过程的膜转运蛋白之间复杂的相互作用，在更大的机制背景下阐明了药物外排。我们的结论是，有关分枝杆菌转运蛋白的大量数据不足以区分它们通过什么机制导致耐药性。最近的研究表明，一些药物流出泵运输分枝杆菌细胞壁的结构脂质，并且某些药物流出抑制剂的作用涉及质子动力的耗散，从而耗尽所有活性膜转运蛋白的能量来源。我们提出关于药物流出数据的生成和解释的建议，以减少歧义并促进为分枝杆菌膜转运蛋白赋予新的作用。本综述概述了分枝杆菌药物流出泵，并提出了有关如何进行和解释药物流出实验的建议。
Mycobacterium tuberculosis (Mtb) can withstand months of antibiotic treatment. An important goal of tuberculosis research is to shorten the treatment to reduce the burden on patients, increase adherence to the drug regimen and thereby slow down the spread of drug resistance. Inhibition of drug efflux pumps by small molecules has been advocated as a promising strategy to attack persistent Mtb and shorten therapy. Although mycobacterial drug efflux pumps have been broadly investigated, mechanistic studies are scarce. In this critical review, we shed light on drug efflux in its larger mechanistic context by considering the intricate interplay between membrane transporters annotated as drug efflux pumps, membrane energetics, efflux inhibitors and cell wall biosynthesis processes. We conclude that a great wealth of data on mycobacterial transporters is insufficient to distinguish by what mechanism they contribute to drug resistance. Recent studies suggest that some drug efflux pumps transport structural lipids of the mycobacterial cell wall and that the action of certain drug efflux inhibitors involves dissipation of the proton motive force, thereby draining the energy source of all active membrane transporters. We propose recommendations on the generation and interpretation of drug efflux data to reduce ambiguities and promote assigning novel roles to mycobacterial membrane transporters. This review provides an overview of mycobacterial drug efflux pumps and sets out recommendations on how to perform and interpret drug efflux experiments.
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DOI：
10.1016/s0006-291x(88)81321-4
发表时间：
1988-06-30
影响因子：
3.1
作者：
BECK, WT;CIRTAIN, MC;SAFA, AR
通讯作者：
SAFA, AR
影响因子：
3.4
作者：
Bauer, Martin;Wulkersdorfer, Beatrix;Langer, Oliver
通讯作者：
Langer, Oliver
影响因子：
3.7
作者：
Bianco, Maria V.;Blanco, Federico C.;Bigi, Fabiana
通讯作者：
Bigi, Fabiana
由巨噬细胞诱导的外排机制介导的复制分枝杆菌的药物耐受性。
影响因子：
64.5
作者：
Adams KN;Takaki K;Connolly LE;Wiedenhoft H;Winglee K;Humbert O;Edelstein PH;Cosma CL;Ramakrishnan L
通讯作者：
Ramakrishnan L
影响因子：
6.4
作者：
Blair JM;Piddock LJ
通讯作者：
Piddock LJ