Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

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 Mycobacterium tuberculosis (Mtb),
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 Mtb DNA gyrase (e.g., compound 42 with IC50 =
2.0) and lower Mtb minimum inhibitor concentrations
(0.49 μM for 42). Notably, 42 and
analogues showed selective Mtb 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 Mtb DNA gyrase was developed, and a structural hypothesis was built
for structure–activity relationship expansion.