Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG

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Mori, Giorgia ^[1] ; Chiarelli, Laurent R. ^[1] ; Esposito, Marta ^[1] ; Makarov, Vadim ^[2] ; Bellinzoni, Marco ^[3] ; Hartkoorn, Ruben C. ^[4] ; Degiacomi, Giulia ^[5] ; Boldrin, Francesca ^[5] ; Ekins, Sean ^[6] ; Lopes Ribeiro, Ana Luisa de Jesus ^[1] ; Marino, Leonardo B. ^{[7, 8]} ; Centarova, Ivana ^[9] ; Svetlikova, Zuzana ^[9] ; Blasko, Jaroslav ^[10] ; Kazakova, Elena ^[2] ; Lepioshkin, Alexander ^[2] ; Barilone, Nathalie ^[3] ; Zanoni, Giuseppe ^[11] ; Porta, Alessio ^[11] ; Fondi, Marco ^[12] ; Fani, Renato ^[12] ; Baulard, Alain R. ^[13] ; Mikusova, Katarina ^[9] ; Alzari, Pedro M. ^[3] ; Manganelli, Riccardo ^[5] ; de Carvalho, Luiz Pedro S. ^[7] ; Riccardi, Giovanna ^[1] ; Cole, Stewart T. ^[4] ; Pasca, Maria Rosalia ^[1]

Afiliação do(s) autor(es):Mostrar menos -

^[1] Univ Pavia, Dept Biol & Biotechnol Lazzaro Spallanzani, I-27100 Pavia - Italy

^[2] Russian Acad Sci, AN Bakh Biochem Inst, Moscow 119071 - Russia

^[3] Univ Paris Diderot, Sorbonne Paris Cite, Unite Microbiol Struct, CNRS UMR3528, Inst Pasteur, F-75724 Paris 15 - France

^[4] Ecole Polytech Fed Lausanne, Global Hlth Inst, Stn 19, CH-1015 Lausanne - Switzerland

^[5] Univ Padua, Dept Mol Med, I-35128 Padua - Italy

^[6] Collaborat Drug Discovery, Burlingame, CA 94010 - USA

^[7] Francis Crick Inst, Mill Hill Lab, London NW7 1AA - England

^[8] Univ Estadual Paulista, UNESP, Fac Pharmaceut Sci, BR-14801902 Araraquara, SP - Brazil

^[9] Comenius Univ, Fac Nat Sci, Dept Biochem, Bratislava 84215 - Slovakia

^[10] Comenius Univ, Fac Nat Sci, Inst Chem, Bratislava 84215 - Slovakia

^[11] Univ Pavia, Dept Chem, I-27100 Pavia - Italy

^[12] Univ Florence, Dept Biol, I-50019 Florence - Italy

^[13] Inst Pasteur, Ctr Infect & Immun, F-59019 Lille - France

• Tipo de documento: Artigo Científico
• Fonte: CHEMISTRY & BIOLOGY; v. 22, n. 7, p. 917-927, JUL 23 2015.
• Citações Web of Science: 29

Resumo

To 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) carba-mothioyl] 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. (AU)

• Processo FAPESP: 11/21232-1 - Avaliação do envolvimento de eIF5A na via secretória em Saccharomyces cerevisiae
• Beneficiário: Leonardo Biancolino Marino
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto