Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Victoria, 3051, Australia.
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
Sci Rep. 2018 Oct 18;8(1):15356. doi: 10.1038/s41598-018-33370-6.
Genomic studies of Mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti-tuberculosis drugs. However, the molecular consequences of polymorphism within these candidate loci remain poorly understood. To address this, we have used computational tools to quantify the effects of point mutations conferring resistance to three major anti-tuberculosis drugs, isoniazid (n = 189), rifampicin (n = 201) and D-cycloserine (n = 48), within their primary targets, katG, rpoB, and alr. Notably, mild biophysical effects brought about by high incidence mutations were considered more tolerable, while different structural effects brought about by haplotype combinations reflected differences in their functional importance. Additionally, highly destabilising mutations such as alr Y388, highlighted a functional importance of the wildtype residue. Our qualitative analysis enabled us to relate resistance mutations onto a theoretical landscape linking enthalpic changes with phenotype. Such insights will aid the development of new resistance-resistant drugs and, via an integration into predictive tools, in pathogen surveillance.
结核分枝杆菌的基因组研究揭示了与抗结核药物耐药性相关的基因座。然而，这些候选基因座内多态性的分子后果仍知之甚少。为了解决这个问题，我们使用计算工具来量化导致三种主要抗结核药物（异烟肼（n=189）、利福平（n=201）和 D-环丝氨酸（n=48））耐药的点突变在其主要靶点 katG、rpoB 和 alr 内的影响。值得注意的是，高发生率突变引起的温和生物物理效应被认为更耐受，而由单倍型组合引起的不同结构效应反映了它们功能重要性的差异。此外，高度不稳定的突变，如 alr Y388，突出了野生型残基的功能重要性。我们的定性分析使我们能够将耐药性突变与连接焓变与表型的理论景观联系起来。这些见解将有助于开发新的耐药性药物，并通过整合到预测工具中，用于病原体监测。
