Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity br

New antibiotics with either a novel mode of actionor novel mode of inhibition are urgently needed to overcome thethreat of drug-resistant tuberculosis (TB). The present studyprofiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitorshaving activity against drug-resistantMycobacterium tuberculosis(Mtb), the causative agent of TB. While the clinical candidatezoliflodacin has progressed to phase 3 trials for the treatment ofgonorrhea, compounds herein demonstrated higher inhibitorypotency againstMtbDNA gyrase (e.g., compound42with IC50=2.0) and lowerMtbminimum inhibitor concentrations (0.49 mu Mfor42). Notably,42and analogues showed selectiveMtbactivityrelative to representative Gram-positive and Gram-negativebacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supportedby hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs withMtbDNA gyrase was developed, and astructural hypothesis was built for structure-activity relationship expansion