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Analysis of mutations in pncA reveals non-overlapping patterns among various lineages of Mycobacterium tuberculosis.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Baddam, Ramani 
Kumar, Narender 
Wieler, Lothar H 
Lankapalli, Aditya Kumar 
Ahmed, Niyaz 

Abstract

Pyrazinamide (PZA) is an important first-line anti-tuberculosis drug, resistance to which occurs primarily due to mutations in pncA (Rv2043c) that encodes the pyrazinamidase enzyme responsible for conversion of pro-drug PZA into its active form. Previous studies have reported numerous resistance-conferring mutations distributed across the entire length of pncA without any hotspot regions. As different lineages of Mycobacterium tuberculosis display a strong geographic association, we sought to understand whether the genetic background influenced the distribution of mutations in pncA. We analyzed the whole genome sequence data of 1,480 clinical isolates representing four major M. tuberculosis lineages to identify the distribution of mutations in the complete operon (Rv2044c-pncA-Rv2042c) and its upstream promoter region. We observed a non-overlapping pattern of mutations among various lineages and identified a lineage 3-specific frame-shift deletion in gene Rv2044c upstream of pncA that disrupted the stop codon and led to its fusion with pncA. This resulted in the addition of a novel domain of unknown function (DUF2784) to the pyrazinamidase enzyme. The variant molecule was computationally modelled and physico-chemical parameters determined to ascertain stability. Although the functional impact of this mutation remains unknown, its lineage specific nature highlights the importance of genetic background and warrants further study.

Description

Keywords

Amidohydrolases, Antitubercular Agents, Cell Lineage, Humans, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, Protein Conformation, Pyrazinamide, Tuberculosis, Multidrug-Resistant

Journal Title

Sci Rep

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

8

Publisher

Nature Publishing Group
Sponsorship
Wellcome Trust (098600/Z/12/Z)
Medical Research Council (MR/N501864/1)