Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Associated With Pyrazinamide Resistance.

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ID: 107162
2019
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Ranked #13 of 41 articles by views in Frontiers in bioengineering and biotechnology

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Abstract
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.
Reference Key
mehmood2019structuralfrontiers Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Mehmood, Aamir;Khan, Muhammad Tahir;Kaushik, Aman Chandra;Khan, Anwar Sheed;Irfan, Muhammad;Wei, Dong-Qing;
Journal Frontiers in bioengineering and biotechnology
Year 2019
DOI
10.3389/fbioe.2019.00404
URL
Keywords
Simulation Drug resistance mtb mutations pza

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