Mehmood Aamir, Khan Muhammad Tahir, Kaushik Aman Chandra, Khan Anwar Sheed, Irfan Muhammad, Wei Dong-Qing
The State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Department of Bioinformatics and Biosciences, Capital University of Science and Technology, Islamabad, Pakistan.
Front Bioeng Biotechnol. 2019 Dec 10;7:404. doi: 10.3389/fbioe.2019.00404. eCollection 2019.
Pyrazinamide (PZA) is one of the main FDA approved drugs to be used as the first line of defense against (MTB). It is activated into pyrazinoic acid (POA) via MTB's gene-encoded pyrazinamidase (PZase). Mutations are most commonly responsible for PZA-resistance in nearly 70% of the resistant samples. In the present work, MTB positive samples were chosen for PZA drug susceptibility testing (DST) against critical concentration (100 ug/ml) of PZA. The resistant samples were subjected to sequencing. As a result, 36 various mutations have been observed in the PZA resistant samples, uploaded to the NCBI (GeneBank accession no. MH461111). Here we report the mechanism of PZA resistance behind the three mutants (MTs), Asp12Ala, Pro54Leu, and His57Pro in comparison with the wild type (WT) through molecular dynamics simulation to unveil how these mutations affect the overall conformational stability. The post-simulation analyses revealed notable deviations as compared to the WT structure. Molecular docking studies of PZA with MTs and WT, pocket volume inspection and overall shape complementarity analysis confirmed the deleterious nature of these mutations and gave an insight into the mechanism behind PZA-resistance. These analyses provide vital information regarding MTB drug resistance and could be extremely useful in therapy management and overcoming its global burden.
吡嗪酰胺（PZA）是美国食品药品监督管理局（FDA）批准的主要药物之一，用作对抗结核分枝杆菌（MTB）的一线防御药物。它通过MTB的基因编码吡嗪酰胺酶（PZase）激活为吡嗪酸（POA）。在近70%的耐药样本中，突变是导致PZA耐药的最常见原因。在本研究中，选择MTB阳性样本针对PZA的临界浓度（100μg/ml）进行PZA药物敏感性测试（DST）。对耐药样本进行测序。结果，在PZA耐药样本中观察到36种不同的突变，并上传至NCBI（基因库登录号MH461111）。在此，我们通过分子动力学模拟报告与野生型（WT）相比，三个突变体（MTs）Asp12Ala、Pro54Leu和His57Pro背后的PZA耐药机制，以揭示这些突变如何影响整体构象稳定性。模拟后分析显示与WT结构相比存在显著偏差。PZA与MTs和WT的分子对接研究、口袋体积检查和整体形状互补性分析证实了这些突变的有害性质，并深入了解了PZA耐药背后的机制。这些分析提供了有关MTB耐药性的重要信息，在治疗管理和克服其全球负担方面可能非常有用。
