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dc.contributor.authorMugumbate, Gen
dc.contributor.authorSilva E Costa Mendes, Vitoren
dc.contributor.authorBlaszczyk, Michalen
dc.contributor.authorSabbah, Men
dc.contributor.authorPapadatos, Gen
dc.contributor.authorLelievre, Jen
dc.contributor.authorBallell, Len
dc.contributor.authorBarros, Den
dc.contributor.authorAbell, Chrisen
dc.contributor.authorBlundell, Tomen
dc.contributor.authorOverington, JPen
dc.date.accessioned2018-02-02T09:17:31Z
dc.date.available2018-02-02T09:17:31Z
dc.date.issued2017-09-26en
dc.identifier.issn1663-9812
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/271509
dc.description.abstractMycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC50 below 50 μM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.
dc.description.sponsorshipGM is grateful to the European Molecular Biology Laboratory and Marie Sklodowska-Curie Actions for funding this work. VM and MB acknowledge Bill & Melinda Gates Foundation [subcontract by the Foundation for the National Institutes of Health (NIH)] (OPP1024021). VM and MS acknowledge the European Community’s Seventh Framework Programme [grant number 260872]. GP would like to acknowledge the Wellcome Trust and the European Molecular Biology Laboratory for funding. JPO was funded by the member nation states of the European Molecular Biology Laboratory. TLB acknowledges The Wellcome Trust for funding and support (grant number 200814/Z/16/Z).
dc.languageEnglishen
dc.publisherFrontiers Media
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectmycobacterium tuberculosisen
dc.subjecttuberculosisen
dc.subjectphenotypic hitsen
dc.subjecttarget identificationen
dc.subjectin silico target predictionen
dc.subjecttarget deconvolutionen
dc.subjectdrug resistanceen
dc.subjectEthRen
dc.subjectInhAen
dc.titleTarget identification of $\textit{Mycobacterium tuberculosis phenotypic}$ hits using a concerted chemogenomic, biophysical and structural approachen
dc.typeArticle
prism.number681en
prism.publicationDate2017en
prism.publicationNameFrontiers in Pharmacologyen
prism.volume8en
dc.identifier.doi10.17863/CAM.18501
dcterms.dateAccepted2017-09-12en
rioxxterms.versionofrecord10.3389/fphar.2017.00681en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-09-26en
dc.contributor.orcidSilva E Costa Mendes, Vitor [0000-0002-2734-2444]
dc.contributor.orcidAbell, Chris [0000-0001-9174-1987]
dc.contributor.orcidBlundell, Tom [0000-0002-2708-8992]
dc.identifier.eissn1663-9812
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idEC FP7 CP (260872)
pubs.funder-project-idMRC (MR/M026302/1)
pubs.funder-project-idMedical Research Council (MR/N501864/1)
pubs.funder-project-idWELLCOME TRUST (200814/Z/16/Z)
datacite.issupplementedby.doi10.17863/CAM.13199en
cam.orpheus.successThu Jan 30 13:00:12 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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