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Antimicrobial Agents and Chemotherapy, July 2008, p. 2324-2334, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01651-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Microbiology Profiling Studies with Staphylococci and Streptococci

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 19 March 2008/ Accepted 22 April 2008

We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC₉₀s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 µg/ml. Against Staphylococcus aureus, CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and >8.5 h determined for the PAE (3x MIC), SME (0.12x MIC), and PAE-SME (3x MIC/0.12x MIC) periods, respectively. Studies of genetically defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 µg/ml and a resistance frequency of <10^–12 determined at 1 µg/ml in agar for S. aureus. Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of S. aureus, CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.

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: Studies of the Mode of Action in Staphylococcus aureus. Antimicrob. Agents Chemother. 52: 2313-2323 [Abstract] [Full Text]