A series of Spiropyrimidinetriones that enhances DNA cleavage mediated by Mycobacterium tuberculosis gyrase

Byl, Jo Ann W., Mueller, Rudolf, Bax, Ben ORCID: https://orcid.org/0000-0003-1940-3785, Basarab, Gregory S., Chibale, Kelly and Osheroff, Neil 2023. A series of Spiropyrimidinetriones that enhances DNA cleavage mediated by Mycobacterium tuberculosis gyrase. ACS Infectious Diseases 9 (3) , pp. 706-715. 10.1021/acsinfecdis.3c00012

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Abstract

The rise in drug-resistant tuberculosis has necessitated the search for alternative antibacterial treatments. Spiropyrimidinetriones (SPTs) represent an important new class of compounds that work through gyrase, the cytotoxic target of fluoroquinolone antibacterials. The present study analyzed the effects of a novel series of SPTs on the DNA cleavage activity of Mycobacterium tuberculosis gyrase. H3D-005722 and related SPTs displayed high activity against gyrase and increased levels of enzyme-mediated double-stranded DNA breaks. The activities of these compounds were similar to those of the fluoroquinolones, moxifloxacin, and ciprofloxacin and greater than that of zoliflodacin, the most clinically advanced SPT. All the SPTs overcame the most common mutations in gyrase associated with fluoroquinolone resistance and, in most cases, were more active against the mutant enzymes than wild-type gyrase. Finally, the compounds displayed low activity against human topoisomerase IIα. These findings support the potential of novel SPT analogues as antitubercular drugs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Chemical Society
ISSN:	2373-8227
Date of First Compliant Deposit:	6 March 2023
Date of Acceptance:	20 February 2023
Last Modified:	03 May 2023 20:39
URI:	https://orca.cardiff.ac.uk/id/eprint/157504

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