There is an urgent need for new antibacterialdrugs that are effectiveagainst infections caused by multidrug-resistant pathogens. Novelnonfluoroquinolone inhibitors of bacterial type II topoisomerases(DNA gyrase and topoisomerase IV) have the potential to become suchdrugs because they display potent antibacterial activity and exhibitno target-mediated cross-resistance with fluoroquinolones. Bacterialtopoisomerase inhibitors that are built on a tetrahydropyran ringlinked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolateswith clinically relevant resistance phenotypes. For instance, analog 49cwas found to be a dual DNA gyrase–topoisomeraseIV inhibitor, with broad antibacterial activity and low propensityfor spontaneous resistance development, but suffered from high hERGK+channel block. On the other hand, analog 49edisplayed lower hERG K+channel block while retainingpotent in vitro antibacterial activity and acceptable frequency forresistance development. Furthermore, analog 49eshowedmoderate clearance in rat and promising in vivo efficacy against Staphylococcus aureusin a murine infection model. [ABSTRACT FROM AUTHOR]