In vitro and in vivo activity of OSUAB-0284, a preclinical candidate for Staphylococcus aureus infections.

Staphylococcus aureus remains one of the world's deadliest pathogens. OSUAB-0284 (284) is a novel, small-molecule anti-staphylococcal agent targeting bacterial type II topoisomerases. 284 inhibited supercoiling by DNA gyrase and decatenation by topoisomerase IV with similar (balanced) potency (IC50 values of 0.80 and 0.15 μM, respectively) and promoted the accumulation of single-strand DNA breaks mediated by DNA gyrase and topoisomerase IV. Cryo-electron microscopy of 284 in ternary complex with 20-bp DNA and S. aureus DNA gyrase elucidated the binding mode. 284 displayed impressive activity against a panel of 100 recent clinical isolates of S. aureus, with a minimal inhibitory concentration (MIC90) of 0.25 μg/mL. Spontaneous frequency of resistance studies indicated a very low rate of resistance selection (<9.62 × 10-10). In vitro studies of absorption, distribution, metabolism, excretion, and toxicity and in vivo pharmacokinetics studies in mice and rats revealed favorable properties for further development. 284 was efficacious in a thigh infection model using neutropenic mice, with twice-daily oral doses ≥50 mg/kg demonstrating ~1 log10 reduction in bacterial colony-forming units. Preliminary safety studies in rats demonstrated that 284 was well tolerated up to the highest tested oral dose of 1,000 mg/kg. 284 is currently in preclinical development as a novel anti-staphylococcal therapy.