Novel katG mutations causing isoniazid resistance in clinical M. tuberculosis isolates.
Novel katG mutations causing isoniazid resistance in clinical M. tuberculosis isolates.
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DOI：
10.1038/emi.2015.42
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发表时间：
2015-07
影响因子：
13.2
通讯作者：
Valafar F
中科院分区：
文献类型：
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作者：
Torres JN;Paul LV;Rodwell TC;Victor TC;Amallraja AM;Elghraoui A;Goodmanson AP;Ramirez-Busby SM;Chawla A;Zadorozhny V;Streicher EM;Sirgel FA;Catanzaro D;Rodrigues C;Gler MT;Crudu V;Catanzaro A;Valafar F
我们报告了23个新的突变的发现和确认，以前没有记录的作用，异烟肼（INH）耐药，在过氧化氢酶-过氧化物酶（katG）基因的结核分枝杆菌（Mtb）分离株。通过这些突变，fabG 1g 609 a中的同义突变和两个典型突变，我们能够解释从四个结核病（TB）高负担国家（印度，摩尔多瓦，菲律宾和南非）收集的366个临床Mtb分离株中观察到的98%的表型耐药。我们进行了重叠靶向和全基因组测序，以发现所有具有各种INH耐药表型的临床分离株的变异体。我们的分析表明，只有两个典型的突变（katG 315 AGC-ACC和inhA启动子-15 C-T）确定了我们收集的89.5%的耐药表型。包括23个新的突变，在这里报告，和以前记录的点突变fabG 1，增加了这些突变的敏感性，作为标志物的异烟肼耐药的98%。在我们收集的332株耐药分离株中，只有6株（2%）没有携带一种或多种这些突变。第三个最普遍的取代，在inhA启动子位置-8，存在于39个耐药菌株，是没有诊断意义，因为它总是与katG 315共同发生。79%的携带新突变的分离株属于遗传组1，表明该组更倾向于走上不寻常的进化道路并逃避分子诊断。本研究的结果有助于我们了解缺乏典型突变的Mtb分离株中INH耐药的机制，并可提高下一代分子诊断的灵敏度。
We report the discovery and confirmation of 23 novel mutations with previously undocumented role in isoniazid (INH) drug resistance, in catalase-peroxidase (katG) gene of Mycobacterium tuberculosis (Mtb) isolates. With these mutations, a synonymous mutation in fabG1g609a, and two canonical mutations, we were able to explain 98% of the phenotypic resistance observed in 366 clinical Mtb isolates collected from four high tuberculosis (TB)-burden countries: India, Moldova, Philippines, and South Africa. We conducted overlapping targeted and whole-genome sequencing for variant discovery in all clinical isolates with a variety of INH-resistant phenotypes. Our analysis showed that just two canonical mutations (katG 315AGC-ACC and inhA promoter-15C-T) identified 89.5% of resistance phenotypes in our collection. Inclusion of the 23 novel mutations reported here, and the previously documented point mutation in fabG1, increased the sensitivity of these mutations as markers of INH resistance to 98%. Only six (2%) of the 332 resistant isolates in our collection did not harbor one or more of these mutations. The third most prevalent substitution, at inhA promoter position -8, present in 39 resistant isolates, was of no diagnostic significance since it always co-occurred with katG 315. 79% of our isolates harboring novel mutations belong to genetic group 1 indicating a higher tendency for this group to go down an uncommon evolutionary path and evade molecular diagnostics. The results of this study contribute to our understanding of the mechanisms of INH resistance in Mtb isolates that lack the canonical mutations and could improve the sensitivity of next generation molecular diagnostics.