Journal article
Bacillus anthracis GrlA(V96A) Topoisomerase IV, a Quinolone Resistance Mutation That Does Not Affect the Water-Metal Ion Bridge
Antimicrobial agents and chemotherapy, Vol.58(12), pp.7182-7187
12/01/2014
DOI: 10.1128/AAC.03734-14
PMCID: PMC4249509
PMID: 25246407
Abstract
The rise in quinolone resistance is threatening the clinical use of this important class of broad-spectrum antibacterials. Quinolones kill bacteria by increasing the level of DNA strand breaks generated by the type II topoisomerases gyrase and topoisomerase IV. Most commonly, resistance is caused by mutations in the serine and acidic amino acid residues that anchor a water-metal ion bridge that facilitates quinolone-enzyme interactions. Although other mutations in gyrase and topoisomerase IV have been reported in quinolone-resistant strains, little is known regarding their contributions to cellular quinolone resistance. To address this issue, we characterized the effects of the V96A mutation in the A subunit of Bacillus anthracis topoisomerase IV on quinolone activity. The results indicate that this mutation causes an similar to 3-fold decrease in quinolone potency and reduces the stability of covalent topoisomerase IV-cleaved DNA complexes. However, based on metal ion usage, the V96A mutation does not disrupt the function of the water-metal ion bridge. A similar level of resistance to quinazolinediones (which do not use the bridge) was seen. V96A is the first topoisomerase IV mutation distal to the water-metal ion bridge demonstrated to decrease quinolone activity. It also represents the first A subunit mutation reported to cause resistance to quinazolinediones. This cross-resistance suggests that the V96A change has a global effect on the structure of the drug-binding pocket of topoisomerase IV.
Details
- Title: Subtitle
- Bacillus anthracis GrlA(V96A) Topoisomerase IV, a Quinolone Resistance Mutation That Does Not Affect the Water-Metal Ion Bridge
- Creators
- Katie J. Aldred - Vanderbilt UniversityErin J. Breland - Vanderbilt UniversitySylvia A. McPherson - University of Alabama at BirminghamCharles L. Turnbough - University of Alabama at BirminghamRobert J. Kerns - University of IowaNeil Osheroff - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.58(12), pp.7182-7187
- DOI
- 10.1128/AAC.03734-14
- PMID
- 25246407
- PMCID
- PMC4249509
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Publisher
- Amer Soc Microbiology
- Number of pages
- 6
- Grant note
- I01 Bx002198 / U.S. Veterans Administration; US Department of Veterans Affairs T32CA009582 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01GM033944 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) AI81775; AI87671; GM33944; T32 CA09582; T32 GM007628 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA I01BX002198 / Veterans Affairs; US Department of Veterans Affairs R56AI081775 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 12/01/2014
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365880502771
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