Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes.
Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes.
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DOI：
10.1038/ng.1038
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发表时间：
2011-12-18
期刊：
影响因子：
30.8
通讯作者：
Gagneux, Sebastien
中科院分区：
文献类型：
--
作者：
Comas, Inaki;Borrell, Sonia;Roetzer, Andreas;Rose, Graham;Malla, Bijaya;Kato-Maeda, Midori;Galagan, James;Niemann, Stefan;Gagneux, Sebastien
耐药细菌正在世界范围内出现，尽管它们通常不如药物敏感菌株适合。来自模型系统的数据表明，抗生素耐药性的适应性成本可以通过补偿性突变来减轻。然而，目前的证据表明，补偿性进化在人类群体中耐药细菌的成功中起着重要作用，这一点还很薄弱。在这里，我们描述了一组新的补偿突变的RNA聚合酶的利福平耐药结核分枝杆菌，人类结核病（TB）的病原体。M.携带这些补偿突变的结核菌株在体外表现出高竞争适应性。此外，这些突变与高体内适应性相关，如通过其在患者群体中的相对临床频率所确定的。重要的是，在世界上多药耐药（MDR）结核病发病率最高的国家，超过30%的MDR临床分离株具有这种突变。我们的研究结果支持在全球耐多药结核病流行中的补偿性进化的作用。
Drug-resistant bacteria are emerging worldwide, despite frequently being less fit than drug-susceptible strains. Data from model systems suggest the fitness cost of antimicrobial resistance can be mitigated by compensatory mutations. However, current evidence that compensatory evolution plays any significant role in the success of drug-resistant bacteria in human populations is weak. Here we describe a set of novel compensatory mutations in the RNA polymerase of rifampicin-resistant Mycobacterium tuberculosis, the etiologic agent of human tuberculosis (TB). M. tuberculosis strains harbouring these compensatory mutations exhibited a high competitive fitness in vitro. Moreover, these mutations were associated with high in vivo fitness as determined by their relative clinical frequency across patient populations. Importantly, in countries with the world’s highest incidence of multidrug-resistant (MDR) TB, more than 30% of MDR clinical isolates had such a mutation. Our findings support a role for compensatory evolution in the global epidemics of MDR-TB.
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