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

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

^* To whom correspondence should be addressed. Email: slynch{at}cumbrepharma.com; asimonlynch@gmail.com.

	Abstract

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. Herein we describe mode-of-action studies in Staphylococcus aureus for CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibits rifampin-like potency as an inhibitor of RNA polymerase and is an equipotent inhibitor of DNA gyrase and DNA topoisomerase IV with retention of activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirm 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 exhibit reduced susceptibility to CBR-2092 further substantiate RNA polymerase as the primary cellular target of CBR-2092 with DNA gyrase and DNA topoisomerase IV as secondary and tertiary targets, respectively, in strains exhibiting pre-existing 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.