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 Enterococcus faecalis, Enterococcus faecium and multidrug
resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs):
range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella
pneumoniae (best compound MICs: range, 1–4
μg/mL). Lead compound 7a was identified with favorable
solubility and plasma protein binding, good metabolic stability, selectivity
for bacterial topoisomerases, and no toxicity issues. The crystal
structure of 7a in complex with Pseudomonas
aeruginosa GyrB24 revealed its binding mode at the
ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR
and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately,
in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.