Journal article
Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV
Biochemistry (Easton), Vol.53(34), pp.5558-5567
09/02/2014
DOI: 10.1021/bi500682e
PMCID: PMC4151693
PMID: 25115926
Abstract
Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance has remained elusive. However, recent studies indicate that clinically relevant quinolones interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water-metal ion bridge and that the most common quinolone resistance mutations decrease drug activity by disrupting this bridge. As a first step toward determining whether the water-metal ion bridge is a general mechanism of quinolone-topoisomerase interaction, we characterized drug interactions with wild-type Escherichia coli (Gram-negative) topoisomerase IV and a series of ParC enzymes with mutations (S80L, S80I, S80F, and E84K) in the predicted bridge-anchoring residues. Results strongly suggest that the water-metal ion bridge is essential for quinolone activity against E. coli topoisomerase IV. Although the bridge represents a common and critical mechanism that underlies broad-spectrum quinolone function, it appears to play different roles in B. anthracis and E. coli topoisomerase IV. The water-metal ion bridge is the most important binding contact of clinically relevant quinolones with the Gram-positive enzyme. However, it primarily acts to properly align clinically relevant quinolones with E. coli topoisomerase IV. Finally, even though ciprofloxacin is unable to increase levels of DNA cleavage mediated by several of the Ser80 and Glu84 mutant E. coli enzymes, the drug still retains the ability to inhibit the overall catalytic activity of these topoisomerase IV proteins. Inhibition parallels drug binding, suggesting that the presence of the drug in the active site is sufficient to diminish DNA relaxation rates.
Details
- Title: Subtitle
- Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV
- Creators
- Katie J Aldred - Vanderbilt UniversityErin J BrelandVladislava VlčkováMarie-Paule Strub - National Heart Lung and Blood InstituteKeir C Neuman - National Heart Lung and Blood InstituteRobert J KernsNeil Osheroff - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.53(34), pp.5558-5567
- DOI
- 10.1021/bi500682e
- PMID
- 25115926
- PMCID
- PMC4151693
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Grant note
- T32 CA009582 / NCI NIH HHS GM33944 / NIGMS NIH HHS I01 BX002198 / BLRD VA AI87671 / NIAID NIH HHS R01 GM033944 / NIGMS NIH HHS
- Language
- English
- Date published
- 09/02/2014
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366019902771
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