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, andintracellular 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 spectrometryweidentified 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.
Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG / Mori G.; Chiarelli L.R.; Esposito M.; Makarov V; Bellinzoni M; Hartkoorn RC; Degiacomi G; Boldrin F; Ekins S; de Jesus Lopes Ribeiro AL; Marino LB; Centárová I; Svetlíková Z; Blaško J; Kazakova E; Lepioshkin A; Barilone N; Zanoni G; Porta A; Fondi M; Fani R; Baulard AR; Mikušová K; Alzari PM; Manganelli R; de Carvalho LP; Riccardi G; Cole ST; Pasca MR. - In: CHEMISTRY & BIOLOGY. - ISSN 1074-5521. - STAMPA. - 22:(2015), pp. 917-927. [doi:10.1016/j.chembiol.2015.05.016]
Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG
FONDI, MARCO;FANI, RENATO;
2015
Abstract
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, andintracellular 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 spectrometryweidentified 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.File | Dimensione | Formato | |
---|---|---|---|
Mori et al - Chemistry and Biology 2015.pdf
Accesso chiuso
Descrizione: Mori et al - Chemistry and Biology 2015
Tipologia:
Pdf editoriale (Version of record)
Licenza:
Tutti i diritti riservati
Dimensione
2.82 MB
Formato
Adobe PDF
|
2.82 MB | Adobe PDF | Richiedi una copia |
I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.