Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV <i>via</i> binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound <b>25</b>, which has potent activity against Gram-positive bacteria, a favorable <i>in vitro</i> safety profile, and excellent <i>in vivo</i> pharmacokinetic properties. Compound <b>25</b> was found to be efficacious against fluoroquinolone-sensitive <i>Staphylococcus aureus</i> infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from <i>Klebsiella pneumoniae</i>, compound <b>25</b>, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of <b>25</b> compared to fluoroquinolones.