Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity.
Govender P, Müller R, Singh K, Reddy V, Eyermann CJ, Fienberg S, Ghorpade SR, Koekemoer L, Myrick A, Schnappinger D, Engelhart C, Meshanni J, Byl JAW, Osheroff N, Singh V, Chibale K, Basarab GS.
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.