Thiophenecarboxamide derivatives activated by EthA kill mycobacterium tuberculosis by inhibiting the CTP synthetase PyrG

dc.contributorUniversity of Pavia
dc.contributorRussian Academy of Science
dc.contributorUniversité Paris Diderot
dc.contributorEcole Polytechnique Fédérale de Lausanne
dc.contributorUniversity of Padova
dc.contributorCollaborative Drug Discovery
dc.contributorFrancis Crick Institute
dc.contributorUniversidade Estadual Paulista (Unesp)
dc.contributorComenius University in Bratislava
dc.contributorUniversity of Florence
dc.contributorCenter for Infection and Immunity
dc.creatorMori, Giorgia
dc.creatorChiarelli, Laurent R.
dc.creatorEsposito, Marta
dc.creatorMakarov, Vadim
dc.creatorBellinzoni, Marco
dc.creatorHartkoorn, Ruben C.
dc.creatorDegiacomi, Giulia
dc.creatorBoldrin, Francesca
dc.creatorEkins, Sean
dc.creatorRibeiro, Ana Luisa de Jesus Lopes
dc.creatorMarino, Leonardo B. [UNESP]
dc.creatorCentárová, Ivana
dc.creatorSvetlíková, Zuzana
dc.creatorBlaško, Jaroslav
dc.creatorKazakova, Elena
dc.creatorLepioshkin, Alexander
dc.creatorBarilone, Nathalie
dc.creatorZanoni, Giuseppe
dc.creatorPorta, Alessio
dc.creatorFondi, Marco
dc.creatorFani, Renato
dc.creatorBaulard, Alain R.
dc.creatorMikušová, Katarína
dc.creatorAlzari, Pedro M.
dc.creatorManganelli, Riccardo
dc.creatorCarvalho, Luiz Pedro S. de
dc.creatorRiccardi, Giovanna
dc.creatorCole, Stewart T.
dc.creatorPasca, Maria Rosalia
dc.date2015-12-07T15:36:39Z
dc.date2015-12-07T15:36:39Z
dc.date2015-07-23
dc.date.accessioned2023-09-12T07:36:20Z
dc.date.available2023-09-12T07:36:20Z
dc.identifierhttp://dx.doi.org/10.1016/j.chembiol.2015.05.016
dc.identifierChemistry & Biology, v. 22, n. 7, p. 917-927, 2015.
dc.identifier1879-1301
dc.identifierhttp://hdl.handle.net/11449/131507
dc.identifier10.1016/j.chembiol.2015.05.016
dc.identifier26097035
dc.identifierPMC4521081
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8780786
dc.descriptionTo 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.
dc.descriptionEuropean Community’s Seventh Framework Program
dc.descriptionSlovak Research and Development Agency
dc.descriptionUK Medical Research Council
dc.descriptionBill and Melinda Gates Foundation
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionDepartment of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy
dc.descriptionA. N. Bakh Institute of Biochemistry, Russian Academy of Science, Moscow, Russia
dc.descriptionInstitut Pasteur, Unité de Microbiologie Structurale, CNRS-UMR3528, Université Paris Diderot, Paris, France
dc.descriptionGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
dc.descriptionDepartment of Molecular Medicine, University of Padova, Padua, Italy
dc.descriptionCollaborative Drug Discovery, Bayshore Highway, Burlingame, CA, USA
dc.descriptionFrancis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
dc.descriptionFaculdade de Ciências Farmacêuticas (FCFAR), Universidade Estadual Paulista (UNESP), Araraquara, SP, Brasil
dc.descriptionDepartment of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, Mlynská dolina, Bratislava, Slovakia
dc.descriptionInstitute of Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, Mlynská dolina, Bratislava, Slovak Republic
dc.descriptionDepartment of Chemistry, University of Pavia, Pavia, Italy
dc.descriptionDepartment of Biology, University of Florence, Sesto Fiorentino, Florence, Italy
dc.descriptionInstitut Pasteur de Lille, Center for Infection and Immunity, Lille, France
dc.descriptionFrancis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
dc.descriptionGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
dc.descriptionDepartment of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy
dc.descriptionFaculdade de Ciências Farmacêuticas (FCFAR), Universidade Estadual Paulista (UNESP), Araraquara, SP, Brasil
dc.descriptionEuropean Community’s Seventh Framework Program: 260872
dc.descriptionSlovak Research and Development Agency: DO7RP-0015-11
dc.descriptionUK Medical Research Council: MC_UP_A253_1111
dc.descriptionBill and Melinda Gates Foundation: 49852
dc.descriptionFAPESP: 2011/21232-1
dc.descriptionCNPq: 140079/2013-0
dc.descriptionCAPES: 99999.003125/2014-09
dc.format917-927
dc.languageeng
dc.publisherElsevier B. V.
dc.relationChemistry & Biology
dc.rightsAcesso restrito
dc.sourcePubMed
dc.titleThiophenecarboxamide derivatives activated by EthA kill mycobacterium tuberculosis by inhibiting the CTP synthetase PyrG
dc.typeArtigo


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