Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

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dc.contributor.authorOjo, Kayode K.en
dc.contributor.authorRanade, Ranae M.en
dc.contributor.authorZhang, Zhongshengen
dc.contributor.authorDranow, David M.en
dc.contributor.authorMyers, Janette B.en
dc.contributor.authorChoi, Ryanen
dc.contributor.authorHewitt, Steve Nakazawaen
dc.contributor.authorEdwards, Thomas E.en
dc.contributor.authorDavies, Douglas R.en
dc.contributor.authorLorimer, Donalden
dc.contributor.authorBoyle, Stephen M.en
dc.contributor.authorBarrett, Lynn K.en
dc.contributor.authorBuckner, Frederick S.en
dc.contributor.authorFan, Erkangen
dc.contributor.authorVan Voorhis, Wesley C.en
dc.date.accessioned2018-08-03T19:31:26Zen
dc.date.available2018-08-03T19:31:26Zen
dc.date.issued2016-08-08en
dc.description.abstractWe investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0160350en
dc.identifier.eissn1932-6203en
dc.identifier.issue8en
dc.identifier.othere0160350en
dc.identifier.pmid27500735en
dc.identifier.urihttp://hdl.handle.net/10919/84492en
dc.identifier.volume11en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleBrucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosisen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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