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Antimicrobial Agents and Chemotherapy, July 2008, p. 2313-2323, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01649-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in Staphylococcus aureus

Gregory T. Robertson, Eric J. Bonventre, Timothy B. Doyle, Qun Du, Leonard Duncan, Timothy W. Morris, Eric D. Roche,^¶ Dalai Yan,^|| and A. Simon Lynch^*

Cumbre Pharmaceuticals Inc., 1502 Viceroy Drive, Dallas, Texas 75235-2304

Received 21 December 2007/ Returned for modification 3 March 2008/ Accepted 22 April 2008

Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent S. aureus infections.

Published ahead of print on 28 April 2008.

Present address: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Present address: Vertex Pharmaceuticals Inc., Coralville, IA 52241.

Present address: Bausch & Lomb Inc., Rochester, NY 14609.

^¶ Present address: Healthpoint Ltd., Fort Worth, TX 76107.

^|| Present address: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202.

This article has been cited by other articles:

• Robertson, G. T., Bonventre, E. J., Doyle, T. B., Du, Q., Duncan, L., Morris, T. W., Roche, E. D., Yan, D., Lynch, A. S. (2008). In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Microbiology Profiling Studies with Staphylococci and Streptococci. Antimicrob. Agents Chemother. 52: 2324-2334 [Abstract] [Full Text]