DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Building from our first generation of 4,5,6,7-tetrahydrobenzo[]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from and , with IC values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. The most promising inhibitor, , is active against , and wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 μg/ml, which represents good starting point for development of novel antibacterials.