In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus.
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. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed 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 exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting 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.
Robertson
Gregory T
GT
Cumbre Pharmaceuticals Inc., 1502 Viceroy Drive, Dallas, TX 75235-2304, USA.
Bonventre
Eric J
EJ
Doyle
Timothy B
TB
Du
Qun
Q
Duncan
Leonard
L
Morris
Timothy W
TW
Roche
Eric D
ED
Yan
Dalai
D
Lynch
A Simon
AS
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D004269:DNA, Bacterial / Q000096:biosynthesis; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009154:Mutation; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000096:biosynthesis; D012294:Rifamycins / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C531325:CBR 2092; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D015363:Quinolones; D012329:RNA, Bacterial; D012294:Rifamycins; D059005:Topoisomerase II Inhibitors; D012321:DNA-Directed RNA Polymerases; D027101:DNA Topoisomerase IV