Journal article
Mechanism of Quinolone Action and Resistance
Biochemistry (Easton), Vol.53(10), pp.1565-1574
03/18/2014
DOI: 10.1021/bi5000564
PMCID: PMC3985860
PMID: 24576155
Abstract
Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide use (and overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. Quin tones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome. This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quinolone action against their enzyme targets. It will then discuss the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones. Target-mediated resistance is the most common and clinically significant form of resistance. It is caused by specific mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements that encode proteins that disrupt quinolone-enzyme interactions, alter drug metabolism, or increase quinolone efflux. Chromosome-mediated resistance results from the underexpression of porins or the overexpression of cellular efflux pumps, both of which decrease cellular concentrations of quinolones. Finally, this review will discuss recent advancements in our understanding of how quinolones interact with gyrase and topoisomerase IV and how mutations in these enzymes cause resistance. These last findings suggest approaches to designing new drugs that display improved activity against resistant strains.
Details
- Title: Subtitle
- Mechanism of Quinolone Action and Resistance
- Creators
- Katie J. Aldred - Vanderbilt UniversityRobert J. Kerns - University of IowaNeil Osheroff - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.53(10), pp.1565-1574
- Publisher
- Amer Chemical Soc
- DOI
- 10.1021/bi5000564
- PMID
- 24576155
- PMCID
- PMC3985860
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Number of pages
- 10
- Grant note
- 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) T32 CA09582; AI87671; GM033944 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32CA009582 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01AI087671 / 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
- 03/18/2014
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365904702771
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