Journal article
Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance
Biochemistry (Easton), Vol.56(32), pp.4191-4200
08/15/2017
DOI: 10.1021/acs.biochem.7b00203
PMCID: PMC5560241
PMID: 28708938
Abstract
Gyrase appears to be the primary cellular target for quinolone antibacterials in multiple pathogenic bacteria, including Bacillus anthracis, the causative agent of anthrax. Given the significance of this type II topoisomerase as a drug target, it is critical to understand how quinolones interact with gyrase and how specific mutations lead to resistance. However, these important issues have yet to be addressed for a canonical gyrase. Therefore, we utilized a mechanistic approach to characterize interactions of quinolones with wild-type B. anthracis gyrase and enzymes containing the most common quinolone resistance mutations. Results indicate that clinically relevant quinolones interact with the enzyme through a water-metal ion bridge in which a noncatalytic divalent metal ion is chelated by the C3/C4 keto acid of the drug. In contrast to other bacterial type II topoisomerases that have been examined, the bridge is anchored to gyrase primarily through a single residue (Ser85). Substitution of groups at the quinolone C7 and C8 positions generated drugs that were less dependent on the water-metal ion bridge and overcame resistance. Thus, by analyzing the interactions of drugs with type II topoisomerases from individual bacteria, it may be possible to identify specific quinolone derivatives that can overcome target-mediated resistance in important pathogenic species.
Details
- Title: Subtitle
- Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance
- Creators
- Rachel E. AshleyR. Hunter LindseySylvia A. McPherson - University of Alabama at BirminghamCharles L. Turnbough - University of Alabama at BirminghamRobert J. Kerns - Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa College of Pharmacy, Iowa City, Iowa 52242, United StatesNeil Osheroff - VA Tennessee Valley Healthcare System
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.56(32), pp.4191-4200
- DOI
- 10.1021/acs.biochem.7b00203
- PMID
- 28708938
- PMCID
- PMC5560241
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Grant note
- DOI: 10.13039/100007217, name: Health Services Research and Development, award: I01 Bx002198; DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: AI87671, AI81775; DOI: 10.13039/100000082, name: Division of Graduate Education, award: DGE-0909667; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: GM33944
- Language
- English
- Date published
- 08/15/2017
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366029302771
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