Department of Biochemistry, University of Cambridge, Tennis Court. Rd., Cambridge, CB2 1GA, UK.
Department of Medicine, University of Cambridge, Hills Rd., Cambridge, CB2 0QQ, UK.
Sci Rep. 2019 Jul 16;9(1):10283. doi: 10.1038/s41598-019-46756-x.
Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface.
耐药性结核病（TB）是全球主要死因之一，主要源于结核分枝杆菌基因组的自发突变。了解突变赋予耐药性的机制对于确定新的药物靶点和设计新药至关重要。先前的研究已经报道了许多赋予抗结核药物耐药性的突变，但几乎没有进行系统分析来了解它们的遗传背景以及对药物靶点稳定性和/或相互作用的潜在影响。在这里，我们报告了对来自印度南部一个城市的 98 例临床结核分枝杆菌分离株的全基因组序列数据的分析。该数据集经过表型耐药性筛选并进行测序，以挖掘赋予异烟肼和利福平耐药性的遗传突变。在异烟肼和利福平分离株中最常见的突变分别是 katG 中的 S315T 和 rpoB 中的 S450L。我们使用统计和机器学习方法分析了突变对蛋白质稳定性、蛋白质-蛋白质相互作用和蛋白质-配体相互作用的影响。耐药性突变不仅预测以正位方式靶向活性位点，而且还通过来自远处位点的变构机制起作用，有时甚至在蛋白质-蛋白质界面处。
