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Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons

Gibson, E.G.; Blower, T.R.; Cacho, M.; Bax, B.; Berger, J.M.; Osheroff, N.

Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons Thumbnail


Authors

E.G. Gibson

M. Cacho

B. Bax

J.M. Berger

N. Osheroff



Abstract

Tuberculosis is one of the leading causes of morbidity worldwide, and the incidences of drug resistance and intolerance are prevalent. Thus, there is a desperate need for the development of new antitubercular drugs. Mycobacterium tuberculosis gyrase inhibitors (MGIs) are napthyridone/aminopiperidine-based drugs that display activity against M. tuberculosis cells and tuberculosis in mouse models [Blanco, D., et al. (2015) Antimicrob. Agents Chemother. 59, 1868–1875]. Genetic and mutagenesis studies suggest that gyrase, which is the target for fluoroquinolone antibacterials, is also the target for MGIs. However, little is known regarding the interaction of these drugs with the bacterial type II enzyme. Therefore, we examined the effects of two MGIs, GSK000 and GSK325, on M. tuberculosis gyrase. MGIs greatly enhanced DNA cleavage mediated by the bacterial enzyme. In contrast to fluoroquinolones (which induce primarily double-stranded breaks), MGIs induced only single-stranded DNA breaks under a variety of conditions. MGIs work by stabilizing covalent gyrase-cleaved DNA complexes and appear to suppress the ability of the enzyme to induce double-stranded breaks. The drugs displayed little activity against type II topoisomerases from several other bacterial species, suggesting that these drugs display specificity for M. tuberculosis gyrase. Furthermore, MGIs maintained activity against M. tuberuclosis gyrase enzymes that contained the three most common fluoroquinolone resistance mutations seen in the clinic and displayed no activity against human topoisomerase IIα. These findings suggest that MGIs have potential as antitubercular drugs, especially in the case of fluoroquinolone-resistant disease.

Citation

Gibson, E., Blower, T., Cacho, M., Bax, B., Berger, J., & Osheroff, N. (2018). Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons. ACS Infectious Diseases, 4(8), 1211-1222. https://doi.org/10.1021/acsinfecdis.8b00035

Journal Article Type Article
Acceptance Date May 10, 2018
Online Publication Date May 10, 2018
Publication Date Aug 10, 2018
Deposit Date May 19, 2018
Publicly Available Date Mar 28, 2024
Journal ACS Infectious Diseases
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 4
Issue 8
Pages 1211-1222
DOI https://doi.org/10.1021/acsinfecdis.8b00035

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Copyright Statement
This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Infectious Diseases, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsinfecdis.8b00035





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