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

Blower, Tim R.; Williamson, Benjamin H.; Kerns, Robert J.; Berger, James M.

doi:10.1073/pnas.1525047113

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

Journal Article · Wed Jan 20 00:00:00 EST 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1525047113· OSTI ID:1239411

^[1]; Williamson, Benjamin H. ^[2]; Kerns, Robert J. ^[2]; Berger, James M. ^[3]

Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Durham Univ. (United Kingdom)
Univ. of Iowa, Iowa City, IA (United States)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)

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. Lastly, these concepts point to new approaches for developing quinolone-class compounds that have increased potency against Mtb and the ability to overcome resistance.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH); National Cancer Institute (NCI)

Grant/Contract Number:: AC02-06CH11357; AI87671; R01-CA077373; P41 GM103403; S10 RR029205; ACB-12002; AGM-12006

OSTI ID:: 1239411

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 7; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 138 works

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Anti-Mycobacterium tuberculosis Activity of Esters of Quinoxaline 1,4-Di-N-Oxide Palos, Isidro; Luna-Herrera, Julieta; Lara-Ramírez, Edgar Molecules, Vol. 23, Issue 6 https://doi.org/10.3390/molecules23061453	journal	June 2018
Targeting bacterial topoisomerases: how to counter mechanisms of resistance Tse-Dinh, Yuk-Ching Future Medicinal Chemistry, Vol. 8, Issue 10 https://doi.org/10.4155/fmc-2016-0042	journal	June 2016
CryoEM structures of open dimers of gyrase A in complex with DNA illuminate mechanism of strand passage Soczek, Katarzyna M.; Grant, Tim; Rosenthal, Peter B. eLife, Vol. 7 https://doi.org/10.7554/elife.41215	journal	November 2018
A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance Germe, Thomas; Vörös, Judit; Jeannot, Frederic Nucleic Acids Research, Vol. 46, Issue 8 https://doi.org/10.1093/nar/gky241	journal	March 2018
The genetic background modulates the evolution of fluoroquinolone-resistance in Mycobacterium tuberculosis Castro, Rhastin A. D.; Ross, Amanda; Kamwela, Lujeko Oxford University Press https://doi.org/10.5451/unibas-ep75536	text	January 2020
DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion Bax, Benjamin D.; Murshudov, Garib; Maxwell, Anthony Journal of Molecular Biology, Vol. 431, Issue 18 https://doi.org/10.1016/j.jmb.2019.07.008	journal	August 2019
Recognition of DNA Supercoil Geometry by Mycobacterium tuberculosis Gyrase Ashley, Rachel E.; Blower, Tim R.; Berger, James M. Biochemistry, Vol. 56, Issue 40 https://doi.org/10.1021/acs.biochem.7b00681	journal	September 2017
Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry Wang, Ying-Ren; Chen, Shin-Fu; Wu, Chyuan-Chuan Nucleic Acids Research, Vol. 45, Issue 18 https://doi.org/10.1093/nar/gkx742	journal	August 2017
A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents Blower, Tim R.; Bandak, Afif; Lee, Amy S. Y. Nucleic Acids Research, Vol. 47, Issue 15 https://doi.org/10.1093/nar/gkz579	journal	July 2019
Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase Walker, Scott S.; Labroli, Marc; Painter, Ronald E. PLOS ONE, Vol. 12, Issue 7 https://doi.org/10.1371/journal.pone.0180965	journal	July 2017
Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China Li, Qianlin; Gao, Huixia; Zhang, Zhi Frontiers in Microbiology, Vol. 10 https://doi.org/10.3389/fmicb.2019.01838	journal	August 2019
Synthesis of Pyrazole-Thiobarbituric Acid Derivatives: Antimicrobial Activity and Docking Studies Elshaier, Yaseen; Barakat, Assem; Al-Qahtany, Bander Molecules, Vol. 21, Issue 10 https://doi.org/10.3390/molecules21101337	journal	October 2016

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