In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: microbiology profiling studies with staphylococci and streptococci.

Abstract

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 MIC(90)s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 mug/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 mug/ml and a resistance frequency of <10(-12) determined at 1 mug/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.

• Authors: Gregory T Robertson, Eric J Bonventre, Timothy B Doyle, Qun Du, Leonard Duncan, Timothy W Morris, Eric D Roche, Dalai Yan, A Simon Lynch
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 52 Issue 7 Pg. 2324-34 (Jul 2008) ISSN: 1098-6596 [Electronic] United States
• PMID: 18443106 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• CBR 2092
• Quinolones
• Rifamycins

Topics

• Anti-Bacterial Agents (chemistry, pharmacology)
• Drug Resistance, Bacterial (genetics)
• Humans
• In Vitro Techniques
• Microbial Sensitivity Tests
• Mutation
• Phenotype
• Quinolones (chemistry, pharmacology)
• Rifamycins (chemistry, pharmacology)
• Staphylococcus (drug effects, genetics, isolation & purification)
• Staphylococcus aureus (drug effects, genetics, isolation & purification)
• Staphylococcus epidermidis (drug effects, genetics, isolation & purification)
• Streptococcus (drug effects, genetics, isolation & purification)