Role of the Water-Metal Ion Bridge in Quinolone Interactions with Escherichia coli Gyrase

Hannah E Carter; Baylee Wildman; Heidi A Schwanz; Robert J Kerns; Katie J Aldred

doi:10.3390/ijms24032879

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Role of the Water-Metal Ion Bridge in Quinolone Interactions with Escherichia coli Gyrase

Journal article

Open access

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Role of the Water-Metal Ion Bridge in Quinolone Interactions with Escherichia coli Gyrase

Hannah E Carter, Baylee Wildman, Heidi A Schwanz, Robert J Kerns and Katie J Aldred

International journal of molecular sciences, Vol.24(3), p.2879

02/02/2023

DOI: 10.3390/ijms24032879

PMCID: PMC9917921

PMID: 36769202

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Abstract

Fluoroquinolones are an important class of antibacterials, and rising levels of resistance threaten their clinical efficacy. Gaining a more full understanding of their mechanism of action against their target enzymes-the bacterial type II topoisomerases gyrase and topoisomerase IV-may allow us to rationally design quinolone-based drugs that overcome resistance. As a step toward this goal, we investigated whether the water-metal ion bridge that has been found to mediate the major point of interaction between topoisomerase IV and topoisomerase IV and gyrase, as well as gyrase, exists in gyrase. This is the first investigation of the water-metal ion bridge and its function in a Gram-negative gyrase. Evidence suggests that the water-metal ion bridge does exist in quinolone interactions with this enzyme and, unlike the Gram-positive gyrase, does use both conserved residues (serine and acidic) as bridge anchors. Furthermore, this interaction appears to play a positioning role. These findings raise the possibility that the water-metal ion bridge is a universal point of interaction between quinolones and type II topoisomerases and that it functions primarily as a binding contact in Gram-positive species and primarily as a positioning interaction in Gram-negative species. Future studies will explore this possibility.

Anti-Bacterial Agents - chemistry

Anti-Bacterial Agents - pharmacology

DNA Gyrase

DNA Topoisomerase IV - metabolism

DNA Topoisomerases, Type II - metabolism

Escherichia coli - metabolism

Fluoroquinolones - pharmacology

Metals - chemistry

Quinolones - chemistry

Quinolones - pharmacology

Topoisomerase II Inhibitors - chemistry

Topoisomerase II Inhibitors - pharmacology

Water - chemistry

Details

Title: Subtitle: Role of the Water-Metal Ion Bridge in Quinolone Interactions with Escherichia coli Gyrase
Creators: Hannah E Carter - University of Evansville
Baylee Wildman - University of Evansville
Heidi A Schwanz - University of Iowa
Robert J Kerns - University of Iowa
Katie J Aldred - University of Evansville
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.24(3), p.2879
DOI: 10.3390/ijms24032879
PMID: 36769202
PMCID: PMC9917921
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Grant note: Spring 2016, Summer 2016, Fall 2016 / UExplore Undergraduate Research Program at the University of Evansville AI87671 / National Institutes of Health T32 GM008365 / National Institutes of Health
Language: English
Date published: 02/02/2023
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984366311502771

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