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吲哚烷基三苯基鏻类似物是使细胞膜去极化的杀分枝杆菌剂。

Indolylalkyltriphenylphosphonium Analogues Are Membrane-Depolarizing Mycobactericidal Agents.

作者信息

Li Ming, Nyantakyi Samuel A, Gopal Pooja, Aziz Dinah Binte, Dick Thomas, Go Mei-Lin

机构信息

Department of Medicine and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543.

出版信息

ACS Med Chem Lett. 2017 Oct 9;8(11):1165-1170. doi: 10.1021/acsmedchemlett.7b00287. eCollection 2017 Nov 9.

Abstract

Agents that selectively target the mycobacterial membrane could potentially shorten treatment time for tuberculosis, reduce relapse, and curtail emergence of resistant strains. The lipophilicity and extensive charge-delocalized state of the triphenylphosphonium cation strongly favor accumulation within bacterial membranes. Here, we explored the antimycobacterial activities and membrane-targeting properties of indolylalkyltriphenylphosphonium analogues. The most active analogues preferentially inhibited growth of H37Rv (MIC 2-4 μM) and were bactericidal against BCG (MBC 3 μM). In spite of their propensity to accumulate within membranes, we found no evidence that these compounds permeabilized mycobacterial membranes or induced cell-envelope stress. Our investigations indicated that their bacterical effects stem from sustained depolarization of mycobacterial membranes and ensuing disruptive effects on electron transfer and cell division.

摘要

选择性靶向分枝杆菌膜的药物有可能缩短结核病的治疗时间、减少复发并遏制耐药菌株的出现。三苯基鏻阳离子的亲脂性和广泛的电荷离域状态强烈有利于其在细菌膜内的积累。在此,我们探索了吲哚基烷基三苯基鏻类似物的抗分枝杆菌活性和膜靶向特性。活性最高的类似物优先抑制H37Rv的生长(MIC为2-4 μM),并对卡介苗具有杀菌作用(MBC为3 μM)。尽管它们倾向于在膜内积累,但我们没有发现这些化合物使分枝杆菌膜通透性增加或诱导细胞包膜应激的证据。我们的研究表明,它们的杀菌作用源于分枝杆菌膜的持续去极化以及随之而来的对电子传递和细胞分裂的破坏作用。

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