期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 9, 页码 6903-6925出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00266
关键词
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资金
- Bill and Melinda Gates Foundation [OPP1066878, OPP1024038]
- Division of Intramural Research of the NIAID/NIH
- Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council (SAMRC)
- University of Cape Town
- South African Research Chairs Initiative of the Department of Science and Technology
- U.S. Veterans Administration Merit Review award [I01Bx002198]
- National Institutes of Health [R01 GM126363]
The study found that new spiropyrimidinetriones (SPTs) compounds have high inhibitory potency against drug-resistant Mycobacterium tuberculosis and may have potential therapeutic value for drug-resistant tuberculosis. These compounds exert antimicrobial effects by stabilizing double-cleaved DNA of the DNA gyrase and show high selectivity against drug-resistant tuberculosis bacteria.
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
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