Identification of Novel Inhibitors of Bacterial Translation Elongation Factors
| Autor: | Tavner Delcamp, Hariharan Venkatesan, Jennifer M. Miller, Liu Tang, Keysha Onheiber, Brooke Rhead, Alejandro Santillan, Wolin Ronald L, Leslie A. Gomez, Ekaterina V. Bobkova, Emily M. Stocking, Maithri M. K. Jayasekera, Karen Joy Shaw, John M. Keith, Shaoming Huang |
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| Rok vydání: | 2005 |
| Předmět: |
Indoles
Transcription Genetic Macromolecular Substances Microbial Sensitivity Tests Peptide Elongation Factor Tu Biology Guanidines Chemical library Structure-Activity Relationship chemistry.chemical_compound Gram-Negative Bacteria Prokaryotic translation Structure–activity relationship Pharmacology (medical) Mechanisms of Action: Physiological Effects Pharmacology Indole test Imidazoles Dipeptides Peptide Elongation Factors Genetic translation Anti-Bacterial Agents Gram-Positive Cocci Elongation factor Infectious Diseases Scintillation proximity assay Biochemistry chemistry Protein Biosynthesis Benzimidazoles EF-Tu |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 49:131-136 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.49.1.131-136.2005 |
| Popis: | 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 μM and an MIC for S. aureus ATCC 29213 of 5.6 μg/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. |
| Databáze: | OpenAIRE |
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