Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.
Cell
; 170(2): 249-259.e25, 2017 Jul 13.
Article
em En
| MEDLINE
| ID: mdl-28669536
ABSTRACT
Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is â¼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Tuberculose
/
Benzofuranos
/
Desenho de Fármacos
/
Farmacorresistência Bacteriana
/
Mycobacterium tuberculosis
/
Antituberculosos
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article