New antibiotics with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug-resistant <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against <i>Mtb</i> DNA gyrase (e.g., compound <b>42</b> with IC<sub>50</sub> = 2.0) and lower <i>Mtb</i> minimum inhibitor concentrations (0.49 μM for <b>42</b>). Notably, <b>42</b> and analogues showed selective <i>Mtb</i> activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with <i>Mtb</i> DNA gyrase was developed, and a structural hypothesis was built for structure-activity relationship expansion.