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dc.contributor.authorMunir, Asmaen
dc.contributor.authorKumar, Narenderen
dc.contributor.authorRamalingam, Suresh Babuen
dc.contributor.authorTamilzhalagan, Sembulingamen
dc.contributor.authorShanmugam, Siva Kumaren
dc.contributor.authorPalaniappan, Alangudi Natarajanen
dc.contributor.authorNair, Dinaen
dc.contributor.authorPriyadarshini, Padmaen
dc.contributor.authorNatarajan, Mohanen
dc.contributor.authorTripathy, Srikanthen
dc.contributor.authorRanganathan, Uma Devien
dc.contributor.authorPeacock, Sharonen
dc.contributor.authorParkhill, Julianen
dc.contributor.authorBlundell, Tomen
dc.contributor.authorMalhotra, Sonyen
dc.date.accessioned2019-07-03T23:30:45Z
dc.date.available2019-07-03T23:30:45Z
dc.date.issued2019-07-16en
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/294344
dc.description.abstractDrug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherNature Publishing Group
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectHumansen
dc.subjectMycobacterium tuberculosisen
dc.subjectTuberculosisen
dc.subjectIsoniaziden
dc.subjectRifampinen
dc.subjectCatalaseen
dc.subjectDNA-Directed RNA Polymerasesen
dc.subjectBacterial Proteinsen
dc.subjectAntitubercular Agentsen
dc.subjectDrug Resistance, Bacterialen
dc.subjectAllosteric Regulationen
dc.subjectProtein Conformationen
dc.subjectMutationen
dc.subjectModels, Molecularen
dc.subjectAdulten
dc.subjectIndiaen
dc.subjectProtein Stabilityen
dc.subjectMachine Learningen
dc.subjectWhole Genome Sequencingen
dc.titleIdentification and Characterization of Genetic Determinants of Isoniazid and Rifampicin Resistance in Mycobacterium tuberculosis in Southern India.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameScientific reportsen
prism.startingPage10283
prism.volume9en
dc.identifier.doi10.17863/CAM.41443
dcterms.dateAccepted2019-06-28en
rioxxterms.versionofrecord10.1038/s41598-019-46756-xen
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-07-16en
dc.contributor.orcidPeacock, Sharon [0000-0002-1718-2782]
dc.contributor.orcidParkhill, Julian [0000-0002-7069-5958]
dc.contributor.orcidBlundell, Tom Leon [0000-0002-2708-8992]
dc.identifier.eissn2045-2322
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMedical Research Council (MR/N501864/1)
pubs.funder-project-idBill & Melinda Gates Foundation (via Foundation for the National Institutes of Health (FNIH)) (BLUN17STB)
cam.orpheus.successMon Jun 08 08:23:45 BST 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2022-07-03


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