Identification of novel inhibitors of bacterial translation elongation factors.
Antimicrob Agents Chemother
; 49(1): 131-6, 2005 Jan.
Article
em En
| MEDLINE
| ID: mdl-15616286
ABSTRACT
Bacterial elongation factor Tu (EF-Tu) and EF-Ts are interacting proteins involved in polypeptide chain elongation in protein biosynthesis. A novel scintillation proximity assay for the detection of inhibitors of EF-Tu and EF-Ts, as well as the interaction between them, was developed and used in a high-throughput screen of a chemical library. Several compounds from a variety of chemical series with inhibitory properties were identified, including certain indole dipeptides, benzimidazole amidines, 2-arylbenzimidazoles, N-substituted imidazoles, and N-substituted guanidines. The in vitro activities of these compounds were confirmed in a coupled bacterial transcription-translation assay. Several indole dipeptides were identified as inhibitors of bacterial translation, with compound 2 exhibiting a 50% inhibitory concentration of 14 microM and an MIC for S. aureus ATCC 29213 of 5.6 microg/ml. Structure-activity relationship studies around the dipeptidic indoles generated additional analogs with low micromolar MICs for both gram-negative and gram-positive bacteria. To assess the specificity of antibacterial action, these compounds were evaluated in a metabolic labeling assay with Staphylococcus aureus. Inhibition of translation, as well as limited effects on other macromolecular pathways for some of the analogs studied, indicated a possible contribution from a non-target-based antibacterial mechanism of action.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Alongamento de Peptídeos
/
Fator Tu de Elongação de Peptídeos
/
Dipeptídeos
/
Indóis
/
Antibacterianos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Estados Unidos