Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobactetium tuberculosis
Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobactetium tuberculosis
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DOI：
10.1128/aac.00112-06
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发表时间：
2006-08-01
影响因子：
4.9
通讯作者：
Alland, David
中科院分区：
文献类型：
--
作者：
Hazbon, Manzour Hernando;Brimacombe, Michael;Alland, David
结核分枝杆菌异烟肼耐药的分子基础是复杂的。已在katG、ahpC、inha、kasa和ndh中发现了可能的异烟肼耐药突变。然而，较小的样本量和样本选择中相关的潜在偏差阻碍了临床异烟肼耐药的统计有效和显著的人群遗传学分析的发展。我们首次大规模分析了先前与异烟肼耐药相关的240个等位基因，这些等位基因来自不同的608个异烟肼敏感株和403个异烟肼耐药临床分离株。我们在异烟肼敏感株中检测到12个突变等位基因，表明这些等位基因与异烟肼耐药性无关。然而，katG、ahpC和inha基因突变与异烟肼耐药密切相关，而KasA突变与异烟肼敏感性相关。值得注意的是，异烟肼耐药相关突变的分布在异烟肼单药耐药株和多重耐药株中不同，异烟肼单耐药组中异烟肼耐药突变显著减少。KatG315基因突变在多重耐药菌株中更为常见。相反，inha启动子突变在异烟肼单耐药分离株中明显更常见。我们测试了突变和对不同药物的耐药性之间的相互作用。KatG、ahpC和inha突变与利福平耐药相关，但只有katG315突变与乙胺丁醇耐药相关。KatG315突变与ahpC或inha突变之间以及KasA突变与ahpC突变之间也存在显著的负相关。我们的结果提示，异烟肼耐药性和多药耐药菌株的进化是一个复杂的动态过程，可能受到基因和耐药表型之间相互作用的影响。
The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.