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