2. Academic Validation
  3. A Series of Spiropyrimidinetriones that Enhances DNA Cleavage Mediated by Mycobacterium tuberculosis Gyrase

A Series of Spiropyrimidinetriones that Enhances DNA Cleavage Mediated by Mycobacterium tuberculosis Gyrase

  • ACS Infect Dis. 2023 Feb 20. doi: 10.1021/acsinfecdis.3c00012.
Jo Ann W Byl 1,  Rudolf Mueller 2,  Ben Bax 3,  Gregory S Basarab 2,  Kelly Chibale 2 4,  Neil Osheroff 1 5 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2 Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 3 Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, United Kingdom.
  • 4 South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
  • 5 Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 6 VA Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States.
PMID: 36802491 DOI: 10.1021/acsinfecdis.3c00012
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.

Keywords

DNA cleavage; Mycobacterium tuberculosis; gyrase; spiropyrimidinetrione.

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