Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones

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 Mg -independent stabilization of the DNA cleavage complex with DNA gyrase and i...

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Published inAntimicrobial agents and chemotherapy Vol. 66; no. 4; p. e0219221
Main Authors Basarab, Gregory S, Ghorpade, Sandeep, Gibhard, Liezl, Mueller, Rudolf, Njoroge, Mathew, Peton, Nashied, Govender, Preshendren, Massoudi, Lisa M, Robertson, Gregory Thomas, Lenaerts, Anne J, Boshoff, Helena Ingrid, Joerss, Douglas, Parish, Tanya, Durand-Reville, Thomas F, Perros, Manos, Singh, Vinayak, Chibale, Kelly
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 19.04.2022
Subjects
Antimicrobial Chemotherapy
DNA Gyrase - genetics
Editor's Pick
Experimental Therapeutics
Fluoroquinolones - pharmacology
Fluoroquinolones - therapeutic use
Humans
Mycobacterium tuberculosis
Topoisomerase II Inhibitors - pharmacology
Tuberculosis - drug therapy
spiropyrimidinetrione
drug resistance
Mycobacterium tuberculosis
DNA gyrase
tuberculosis
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Summary: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 Mg -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 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 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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The authors declare no conflict of interest.
ISSN:0066-4804
1098-6596
DOI:10.1128/aac.02192-21