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Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis

Blower, T.R.; Williamson, B.H.; Kerns, R.J.; Berger, J.M.

Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis Thumbnail


Authors

B.H. Williamson

R.J. Kerns

J.M. Berger



Abstract

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are critical agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were determined in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resolution, show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a reduction in contacts to the water shell of an associated magnesium ion, which bridges fluoroquinolone–gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone–enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compounds that have increased potency against Mtb and the ability to overcome resistance.

Citation

Blower, T., Williamson, B., Kerns, R., & Berger, J. (2016). Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences, 113(7), 1706-1713. https://doi.org/10.1073/pnas.1525047113

Journal Article Type Article
Acceptance Date Dec 22, 2015
Online Publication Date Jan 20, 2016
Publication Date Feb 16, 2016
Deposit Date Jan 21, 2016
Publicly Available Date Mar 29, 2024
Journal Proceedings of the National Academy of Sciences
Print ISSN 0027-8424
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 113
Issue 7
Pages 1706-1713
DOI https://doi.org/10.1073/pnas.1525047113
Keywords Mycobacterium tuberculosis, Fluoroquinolones, Antibiotic resistance, Gyrase, Complex stability.

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