Mutations in Genes for the F420 Biosynthetic Pathway and a Nitroreductase Enzyme Are the Primary Resistance Determinants in Spontaneous In Vitro-Selected PA-824-Resistant Mutants of Mycobacterium tuberculosis
Mutations in Genes for the F420 Biosynthetic Pathway and a Nitroreductase Enzyme Are the Primary Resistance Determinants in Spontaneous In Vitro-Selected PA-824-Resistant Mutants of Mycobacterium tuberculosis
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DOI：
10.1128/aac.00308-15
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发表时间：
2015-09-01
影响因子：
4.9
通讯作者：
Bifani, Pablo
中科院分区：
文献类型：
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作者：
Haver, Hana L.;Chua, Adeline;Bifani, Pablo
减轻结核病 (TB) 的负担需要了解决定耐药突变体出现的遗传基础。 PA-824（pretomanid）是一种双环硝基咪唑类化合物，目前正在进行 III 期 STAND 临床试验，尽管缺乏药物特异性耐药结核分枝杆菌的可识别遗传标记。在本研究中，我们旨在通过调查药物代谢基因的潜在突变来表征自发产生的 PA-824 抗性突变株的遗传多态性。在 183 个独立选择的 PA-824 抗性结核分枝杆菌突变体中，83% 在与 PA-824 前药激活（ddn，29%；fgd1，7%）或切向 F-420 生物合成途径（fbiA，19%；fbiB，2%；fbiC，26%）相关的五个非必需基因之一中存在单一突变。晶体结构分析表明，已识别的突变专门位于蛋白质催化结构域内，这会阻碍前药激活所需的酶的活性。对 PA-824 耐药基因型进行的系统分析可能有助于未来监测这种新药物疗法的临床菌株敏感性。
Alleviating the burden of tuberculosis (TB) requires an understanding of the genetic basis that determines the emergence of drug-resistant mutants. PA-824 (pretomanid) is a bicyclic nitroimidazole class compound presently undergoing the phase III STAND clinical trial, despite lacking identifiable genetic markers for drug-specific resistant Mycobacterium tuberculosis. In the present study, we aimed to characterize the genetic polymorphisms of spontaneously generated PA-824-resistant mutant strains by surveying drug metabolism genes for potential mutations. Of the 183 independently selected PA-824-resistant M. tuberculosis mutants, 83% harbored a single mutation in one of five nonessential genes associated with either PA-824 prodrug activation (ddn, 29%; fgd1, 7%) or the tangential F-420 biosynthetic pathway (fbiA, 19%; fbiB, 2%; fbiC, 26%). Crystal structure analysis indicated that identified mutations were specifically located within the protein catalytic domain that would hinder the activity of the enzymes required for prodrug activation. This systematic analysis conducted of genotypes resistant to PA-824 may contribute to future efforts in monitoring clinical strain susceptibility with this new drug therapy.