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

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


jats:titleAbstract</jats:title>jats:pPyrazinamide (PZA) is an important first-line anti-tuberculosis drug, resistance to which occurs primarily due to mutations in jats:italicpncA</jats:italic> (jats:italicRv2043c</jats:italic>) 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 jats:italicpncA</jats:italic> without any hotspot regions. As different lineages of jats:italicMycobacterium tuberculosis</jats:italic> display a strong geographic association, we sought to understand whether the genetic background influenced the distribution of mutations in jats:italicpncA</jats:italic>. We analyzed the whole genome sequence data of 1,480 clinical isolates representing four major jats:italicM. tuberculosis</jats:italic> lineages to identify the distribution of mutations in the complete operon (jats:italicRv2044c-pncA-Rv2042c)</jats:italic> 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 jats:italicRv2044c</jats:italic> upstream of jats:italicpncA</jats:italic> that disrupted the stop codon and led to its fusion with jats:italicpncA</jats:italic>. 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.</jats:p>



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Scientific Reports

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Springer Science and Business Media LLC
Medical Research Council (MR/N501864/1)