期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 66, 期 4, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.02192-21
关键词
spiropyrimidinetrione; Mycobacterium tuberculosis; tuberculosis; DNA gyrase; drug resistance
资金
- Bill and Melinda Gates Foundation [OPP1066878, OPP1024038]
- South African Strategic Health Innovation Partnership unit of the South Africa Medical Research Council (SAMRC)
- Division of Intramural Research of the NIAID/NIH
- University of Cape Town
- SAMRC
- South African Research Chairs Initiative of the Department of Science and Innovation
This article describes a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis by inhibiting DNA gyrase. The SPT class of compounds operates through a novel mode of inhibition, which is not cross-resistant with other DNA gyrase-inhibiting antibacterials. Compound 22 from the series demonstrated in vitro cidality and intracellular activity against M. tuberculosis. The DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response in M. tuberculosis.
Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg2+-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones. Compound 22 from the series was profiled broadly and showed in vitro cidality as well as intracellular activity against M. tuberculosis in macrophages. Evidence for the DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response seen in a recA reporter strain of M. tuberculosis. Pharmacokinetic properties of 22 supported evaluation of efficacy in an acute model of M. tuberculosis infection, where modest reduction in CFU numbers was seen. This work offers promise for deriving a novel drug class of tuberculosis agent without preexisting clinical resistance.
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