结核分枝杆菌贝达喹啉和氯法齐明耐药及其交叉耐药机制研究进展

Progress on the molecular mechanism of independent resistance and cross-resistance to bedaquiline and clofazimine in Mycobacterium tuberculosis

目前,全球结核病耐药现象严重,给结核病的防控工作带来了极大的困难与挑战,并亟需新型抗结核药物来阻止耐药结核病的蔓延。贝达喹啉和氯法齐明分别是世界卫生组织推荐的A组和B组核心抗结核药物,主要用于耐多药结核病的治疗且疗效较好。但近年来贝达喹啉和氯法齐明耐药的现象也时有报道,且二者存在交叉耐药的情况。本文综述了与结核分枝杆菌(Mycobacterium tuberculosis,MTB)对贝达喹啉和氯法齐明独立及交叉耐药相关的基因突变,重点总结与2种药物交叉耐药相关的基因突变。目前,涉及MTB对贝达喹啉和氯法齐明交叉耐药的相关突变基因为Rv0678(mmpR)和Rv2535c(pepQ),均属于非靶基因突变,且会对这2种药物产生低水平耐药。与MTB对贝达喹啉和氯法齐明耐药相关的其他突变基因分别为atpE和Rv1979c,其中atpE为靶基因相关的突变,而Rv1979c导致的耐药机制还不是很清楚。通过综述MTB对贝达喹啉和氯法齐明耐药及交叉耐药的相关机制,以期为贝达喹啉和氯法齐明耐药机制的研究以及其今后在结核病治疗上的应用提供参考。

At present,the drug resistant tuberculosis is relatively high worldwide and has become a serious public health issue.New anti-tuberculosis drugs are urgently needed to prevent the increase of drug resistant tuberculosis.Bedaquiline and clofazimine are core anti-tuberculosis drugs belong to group A and B respectively,and are recommended by World Health Organization(WHO)for the treatment of multi-drug resistant tuberculosis with a good effect.However,Mycobacterium tuberculosis(MTB)that independent resistance and cross-resistance to bedaquiline and clofazimine gradually increased in recent years.This study reviewed the independent resistance and cross-resistance related genes of MTB to bedaquiline and clofazimine,with an emphasis on cross-resistant genes.At present,the gene mutation involved in bedaquiline and clofazimine cross-resistance to MTB are mainly Rv0678(mmpR)and Rv2535c(pepQ)genes,which are non-target related mutation and result in lower-level cross-resistance to the two agents.The independent gene mutation involved in bedaquiline resistance is atpE,which is target related mutation.The independent gene mutation involved in clofazimine resistance is regarded as Rv1979c,although the drug resistant mechanisms is still not clear.The aim of this review is to provide a reference for the study on resistance mechanism of Mycobacterium tuberculosis to bedaquiline and clofazimine and for their further application on tuberculosis treatment.