结核分枝杆菌耐氟喹诺酮类药物的分子机制研究进展  

Mechanisms of fluoroquinolone resistance in Mycobacterium tuberculosis

作　　者：张玉娇[1] 李晓静[1] 米凯霞[1] Yujiao Zhang Xiaojing Li Kaixia Mi(CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences Beijing 100101, China)

机构地区：[1]中国科学院微生物研究所,病原微生物与免疫学重点实验室,北京100101

出　　处：《遗传》2016年第10期918-927,共10页Hereditas（Beijing)

基　　金：国家自然科学基金项目(编号:31270178,31670137)资助~~

摘　　要：结核病是由结核分枝杆菌(Mycobacterium tuberculosis)通过空气传播引起人类感染的慢性传染病,耐药结核分枝杆菌的流行是目前结核病防治的世界难题。氟喹诺酮类药物是人工合成药物,应用于耐药结核的临床治疗中,在治疗中起着核心的作用。但近年来,氟喹诺酮类药物的抗性菌株不断出现,愈发增加了结核病治疗的困难与治疗失败风险。在临床中氟喹诺酮药物的靶点比较清楚,是结核分枝杆菌的DNA旋转酶。目前发现结核分枝杆菌耐氟喹诺酮类药物的机制主要包括药物靶点DNA旋转酶的关键氨基酸改变、药物外排泵系统、细菌细胞壁厚度的增加以及喹诺酮抗性蛋白Mfp A介导的DNA旋转酶活性调控。其中在氟喹诺酮靶标DNA旋转酶功能活性改变的耐药机制方面,编码DNA旋转酶基因突变一直是研究的热点,但近年来发现DNA旋转酶的调控蛋白Mfp A以及DNA旋转酶的修饰在细菌耐药性中起着重要的作用,相关机制还亟待发现。本文综述了当前结核分枝杆菌耐氟喹诺酮类药物的作用机制,旨在为研发精准诊断技术和药物发掘提供科学理论基础和参考。Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is one of the world＇s deadliest bacterial infectious disease. It is still a global-health threat, particularly because of the drug-resistant forms. Fluoroquinolones, with target of gyrase, are among the drugs used to treat tuberculosis. However, their widespread use has led to bacterial resistance. The molecular mechanisms of fluoroquinolone resistance in mycobacterium tuberculosis have been reported, such as DNA gyrase mutations, drug efflux pumps system, bacterial cell wall thickness and pentapeptide proteins（Mfp A） mediated regulation of gyrase. Mutations in gyrase conferring quinolone resistance play important roles and have been extensively studied. Recent studies have shown that the regulation of DNA gyrase affects mycobacterial drug resistance, but the mechanisms, especially by post-translational modification and regulatory proteins, are poorly understood. In this review, we summarize the fluoroquinolone drug development, and the molecular genetics of fluoroquinolone resistance in mycobacteria. Comprehensive understanding of the mechanisms of fluoroquinolone resistance in Mycobacterium tuberculosis will open a new view on understanding drug resistance in mycobacteria and lead to novel strategies to develop new accurate diagnosis methods.

关 键 词：结核分枝杆菌 氟喹诺酮 耐药 DNA旋转酶 

分 类 号：R378.911[医药卫生—病原生物学]