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Sci Rep. 2018 Mar 15;8(1):4628. doi: 10.1038/s41598-018-22883-9.

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

Author information

1
Robert Koch Institute, Berlin, 13353, Germany.
2
Laboratory Sciences and Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh.
3
Department of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
4
Department of Biotechnology and Bioinformatics, Pathogen Biology Laboratory, School of Life Sciences, University of Hyderabad, Hyderabad, 500084, India.
5
Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena, Germany.
6
Laboratory Sciences and Services Division, International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, 1212, Bangladesh.
7
London School of Hygiene and Tropical Medicine, London, WC1E 7HT, United Kingdom.
8
Robert Koch Institute, Berlin, 13353, Germany. SemmlerT@rki.de.

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.

PMID:
29545614
PMCID:
PMC5854631
DOI:
10.1038/s41598-018-22883-9
[Indexed for MEDLINE]
Free PMC Article

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