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Antimicrobial Agents and Chemotherapy, January 2005, p. 131-136, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.131-136.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of Novel Inhibitors of Bacterial Translation Elongation Factors

Maithri M. K. Jayasekera, Keysha Onheiber, John Keith, Hariharan Venkatesan, Alejandro Santillan, Emily M. Stocking, Liu Tang, Jennifer Miller, Leslie Gomez, Brooke Rhead, Tavner Delcamp, Shaoming Huang, Ronald Wolin, Ekaterina V. Bobkova,* and Karen Joy Shaw

Infectious Diseases, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., La Jolla, California

Received 23 April 2004/ Returned for modification 26 June 2004/ Accepted 22 September 2004

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.

* Corresponding author. Mailing address: Johnson & Johnson Pharmaceutical Research and Development, 3210 Merryfield Row, San Diego, CA 92121. Phone: (858) 320-3385. Fax: (858) 450-2094. E-mail: ebobkova{at}prdus.jnj.com.

Antimicrobial Agents and Chemotherapy, January 2005, p. 131-136, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.131-136.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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