| Literature DB >> 35500229 |
Preshendren Govender1, Rudolf Müller1, Kawaljit Singh1, Virsinha Reddy1, Charles J Eyermann1, Stephen Fienberg1, Sandeep R Ghorpade1, Lizbé Koekemoer2, Alissa Myrick2, Dirk Schnappinger3, Curtis Engelhart3, Jaclynn Meshanni3, Jo Ann W Byl4, Neil Osheroff4,5,6, Vinayak Singh1,2, Kelly Chibale1,2, Gregory S Basarab1,7.
Abstract
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.Entities:
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Year: 2022 PMID： 35500229 PMCID： PMC9233935 DOI： 10.1021/acs.jmedchem.2c00266
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039