Show simple item record

dc.contributor.authorBaddam, Ramanien
dc.contributor.authorKumar, Narenderen
dc.contributor.authorWieler, Lothar Hen
dc.contributor.authorLankapalli, Aditya Kumaren
dc.contributor.authorAhmed, Niyazen
dc.contributor.authorPeacock, Sharonen
dc.contributor.authorSemmler, Torstenen
dc.date.accessioned2018-09-26T12:12:15Z
dc.date.available2018-09-26T12:12:15Z
dc.date.issued2018-03-15en
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280740
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.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumansen
dc.subjectMycobacterium tuberculosisen
dc.subjectTuberculosis, Multidrug-Resistanten
dc.subjectPyrazinamideen
dc.subjectAmidohydrolasesen
dc.subjectAntitubercular Agentsen
dc.subjectMicrobial Sensitivity Testsen
dc.subjectProtein Conformationen
dc.subjectCell Lineageen
dc.subjectMutationen
dc.titleAnalysis of mutations in pncA reveals non-overlapping patterns among various lineages of Mycobacterium tuberculosis.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2018en
prism.publicationNameScientific reportsen
prism.startingPage4628
prism.volume8en
dc.identifier.doi10.17863/CAM.28104
dcterms.dateAccepted2018-03-01en
rioxxterms.versionofrecord10.1038/s41598-018-22883-9en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-03-15en
dc.contributor.orcidKumar, Narender [0000-0003-2089-9626]
dc.contributor.orcidWieler, Lothar H [0000-0003-4365-3717]
dc.contributor.orcidPeacock, Sharon [0000-0002-1718-2782]
dc.contributor.orcidSemmler, Torsten [0000-0002-2225-7267]
dc.identifier.eissn2045-2322
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (098600/Z/12/Z)
pubs.funder-project-idMedical Research Council (MR/N501864/1)


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International