New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus .

A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive , and multidrug resistant (MDR) strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives and (best compound MICs: range, 1-4 μg/mL). Lead compound was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of in complex with GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of and showed potent antibacterial activity against over 100 MDR and non-MDR strains of and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of in a mouse model of vancomycin-intermediate thigh infection was also demonstrated.