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dc.contributor.authorMori, Giorgia
dc.contributor.authorChiarelli, Laurent R.
dc.contributor.authorEsposito, Marta
dc.contributor.authorMakarov, Vadim
dc.contributor.authorBellinzoni, Marco
dc.contributor.authorHartkoorn, Ruben C.
dc.contributor.authorDegiacomi, Giulia
dc.contributor.authorBoldrin, Francesca
dc.contributor.authorEkins, Sean
dc.contributor.authorRibeiro, Ana Luisa de Jesus Lopes
dc.contributor.authorMarino, Leonardo B. [UNESP]
dc.contributor.authorCentárová, Ivana
dc.contributor.authorSvetlíková, Zuzana
dc.contributor.authorBlaško, Jaroslav
dc.contributor.authorKazakova, Elena
dc.contributor.authorLepioshkin, Alexander
dc.contributor.authorBarilone, Nathalie
dc.contributor.authorZanoni, Giuseppe
dc.contributor.authorPorta, Alessio
dc.contributor.authorFondi, Marco
dc.contributor.authorFani, Renato
dc.contributor.authorBaulard, Alain R.
dc.contributor.authorMikušová, Katarína
dc.contributor.authorAlzari, Pedro M.
dc.contributor.authorManganelli, Riccardo
dc.contributor.authorCarvalho, Luiz Pedro S. de
dc.contributor.authorRiccardi, Giovanna
dc.contributor.authorCole, Stewart T.
dc.contributor.authorPasca, Maria Rosalia
dc.date.accessioned2015-12-07T15:36:39Z
dc.date.available2015-12-07T15:36:39Z
dc.date.issued2015-07-23
dc.identifierhttp://dx.doi.org/10.1016/j.chembiol.2015.05.016
dc.identifier.citationChemistry & Biology, v. 22, n. 7, p. 917-927, 2015.
dc.identifier.issn1879-1301
dc.identifier.urihttp://hdl.handle.net/11449/131507
dc.description.abstractTo combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target.en
dc.description.sponsorshipEuropean Community’s Seventh Framework Program
dc.description.sponsorshipSlovak Research and Development Agency
dc.description.sponsorshipUK Medical Research Council
dc.description.sponsorshipBill and Melinda Gates Foundation
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.format.extent917-927
dc.language.isoeng
dc.publisherElsevier B. V.
dc.relation.ispartofChemistry & Biology
dc.sourcePubMed
dc.titleThiophenecarboxamide derivatives activated by EthA kill mycobacterium tuberculosis by inhibiting the CTP synthetase PyrGen
dc.typeArtigo
dcterms.rightsHolderElsevier B. V.
dc.contributor.institutionUniversity of Pavia
dc.contributor.institutionRussian Academy of Science
dc.contributor.institutionUniversité Paris Diderot
dc.contributor.institutionEcole Polytechnique Fédérale de Lausanne
dc.contributor.institutionUniversity of Padova
dc.contributor.institutionCollaborative Drug Discovery
dc.contributor.institutionFrancis Crick Institute
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionComenius University in Bratislava
dc.contributor.institutionUniversity of Florence
dc.contributor.institutionCenter for Infection and Immunity
dc.description.affiliationDepartment of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy
dc.description.affiliationA. N. Bakh Institute of Biochemistry, Russian Academy of Science, Moscow, Russia
dc.description.affiliationInstitut Pasteur, Unité de Microbiologie Structurale, CNRS-UMR3528, Université Paris Diderot, Paris, France
dc.description.affiliationGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
dc.description.affiliationDepartment of Molecular Medicine, University of Padova, Padua, Italy
dc.description.affiliationCollaborative Drug Discovery, Bayshore Highway, Burlingame, CA, USA
dc.description.affiliationFrancis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
dc.description.affiliationFaculdade de Ciências Farmacêuticas (FCFAR), Universidade Estadual Paulista (UNESP), Araraquara, SP, Brasil
dc.description.affiliationDepartment of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, Mlynská dolina, Bratislava, Slovakia
dc.description.affiliationInstitute of Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, Mlynská dolina, Bratislava, Slovak Republic
dc.description.affiliationDepartment of Chemistry, University of Pavia, Pavia, Italy
dc.description.affiliationDepartment of Biology, University of Florence, Sesto Fiorentino, Florence, Italy
dc.description.affiliationInstitut Pasteur de Lille, Center for Infection and Immunity, Lille, France
dc.description.affiliationFrancis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
dc.description.affiliationGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
dc.description.affiliationDepartment of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy
dc.description.affiliationUnespFaculdade de Ciências Farmacêuticas (FCFAR), Universidade Estadual Paulista (UNESP), Araraquara, SP, Brasil
dc.identifier.doi10.1016/j.chembiol.2015.05.016
dc.rights.accessRightsAcesso restrito
dc.description.sponsorshipIdEuropean Community’s Seventh Framework Program: 260872
dc.description.sponsorshipIdSlovak Research and Development Agency: DO7RP-0015-11
dc.description.sponsorshipIdUK Medical Research Council: MC_UP_A253_1111
dc.description.sponsorshipIdBill and Melinda Gates Foundation: 49852
dc.description.sponsorshipIdFAPESP: 2011/21232-1
dc.description.sponsorshipIdCNPq: 140079/2013-0
dc.description.sponsorshipIdCAPES: 99999.003125/2014-09
unesp.campusUniversidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquarapt
dc.identifier.pubmed26097035
dc.identifier.pmcPMC4521081
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