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

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

Herein we describe data from antimicrobial assays 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. MIC₉₀ values for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 µg/mL. Against S. aureus, CBR-2092 exhibits prolonged post-antibiotic and sub-MIC effects with values of 3.2, 6.5 and > 8.5 h, respectively, determined for the PAE (3xMIC), SME (0.12xMIC) and PAE-SME (3xMIC/0.12xMIC) periods. Studies of genetically-defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In MBC and time-kill studies, CBR-2092 exhibits bactericidal activity against staphylococci that is retained against rifampin- or intermediate quinolone-resistant strains with apparent paradoxical cidal characteristics versus the former. In spontaneous resistance studies, CBR-2092 exhibits activity consistent with balanced contributions from its composite pharmacophores with a mutant prevention concentration (MPC) 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 suppresses the emergence of pre-existing rifamycin resistance in time-kill studies undertaken at high cell density. In studies of the intracellular killing of S. aureus, CBR-2092 exhibits prolonged bactericidal activity that is superior to moxifloxacin, rifampin or a cocktail thereof. Overall, CBR-2092 exhibits promising activity in a range of antimicrobial assays in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.