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2018-03-15Zeitschriftenartikel DOI: 10.1038/s41598-018-22883-9
Analysis of mutations in pncA reveals non-overlapping patterns among various lineages of Mycobacterium tuberculosis
dc.contributor.authorBaddam, Ramani
dc.contributor.authorKumar, Narender
dc.contributor.authorWieler, Lothar H.
dc.contributor.authorLankapalli, Aditya Kumar
dc.contributor.authorAhmed, Niyaz
dc.contributor.authorPeacock, Sharon J.
dc.contributor.authorSemmler, Torsten
dc.date.accessioned2018-05-07T21:12:28Z
dc.date.available2018-05-07T21:12:28Z
dc.date.created2018-04-03
dc.date.issued2018-03-15none
dc.identifier.otherhttp://edoc.rki.de/oa/articles/reeftTdTgOc2s/PDF/26xDA0pMiQ6b2.pdf
dc.identifier.urihttp://edoc.rki.de/176904/3022
dc.description.abstractPyrazinamide (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.eng
dc.language.isoeng
dc.publisherRobert Koch-Institut
dc.subject.ddc610 Medizin
dc.titleAnalysis of mutations in pncA reveals non-overlapping patterns among various lineages of Mycobacterium tuberculosis
dc.typeperiodicalPart
dc.identifier.urnurn:nbn:de:0257-10058257
dc.identifier.doi10.1038/s41598-018-22883-9
dc.identifier.doihttp://dx.doi.org/10.25646/2947
local.edoc.container-titleScientific Reports
local.edoc.fp-subtypeArtikel
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttps://www.nature.com/articles/s41598-018-22883-9
local.edoc.container-publisher-nameNature Publishing Group
local.edoc.container-volume8
local.edoc.container-issue4628
local.edoc.container-year2018

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