title: 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.affiliation: Cumbre Pharmaceuticals Inc., 1502 Viceroy Drive, Dallas, TX 75235-2304, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Robertson
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bonventre
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Doyle
authors.forename: Qun
authors.initials: Q
authors.lastname: Du
authors.forename: Leonard
authors.initials: L
authors.lastname: Duncan
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Morris
authors.forename: Eric D
authors.initials: ED
authors.lastname: Roche
authors.forename: Dalai
authors.initials: D
authors.lastname: Yan
authors.forename: A Simon
authors.initials: AS
authors.lastname: Lynch
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D012294:Rifamycins / Q000737:chemistry / Q000494:pharmacology*; D013210:Staphylococcus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D013291:Streptococcus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; C531325:CBR 2092; D015363:Quinolones; D012294:Rifamycins