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Bacterial Type II Topoisomerases and Target-Mediated Drug Resistance

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Antimicrobial Resistance in the 21st Century

Part of the book series: Emerging Infectious Diseases of the 21st Century ((EIDC))

Abstract

Fluoroquinolones are one of the most widely prescribed classes of broad-spectrum antibacterials currently in clinical use. These drugs kill bacteria by increasing DNA strand breaks generated by the type II topoisomerases, gyrase and topoisomerase IV. Despite the importance of fluoroquinolones in the treatment of bacterial infections, their usefulness is being diminished by the rise of drug resistance. The most common and clinically relevant form of fluoroquinolone resistance is target-mediated, which is caused by specific mutations in gyrase and topoisomerase IV. Although these mutations were first identified over 30 years ago, the mechanism by which they cause resistance has only recently been established. This knowledge has contributed greatly to our understanding of how fluoroquinolones interact with their enzyme targets and has suggested mechanisms for overcoming resistance. In order to more fully describe target-mediated fluoroquinolone resistance, this article will provide background on the drug class, discuss how gyrase and topoisomerase IV function, describe the basis for fluoroquinolone-enzyme interactions, and discuss how altering these interactions leads to resistance. Finally, new approaches to overcoming target-mediated fluoroquinolone resistance will be discussed.

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Acknowledgments

The authors of this article were supported by the US Veterans Administration (Merit Review Award I01 Bx002198 to N.O.), the National Institutes of Health (grants AI87671 to R.J.K., GM33944 and GM126363 to N.O., and GM007628 to E.G.G.), the National Science Foundation (grant DGE-0909667 to R.E.A.), the Pharmaceutical Research and Manufacturers of America Foundation (to E.G.G.), and the American Association of Pharmaceutical Scientists Foundation (to E.G.G.).

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Authors and Affiliations

  1. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Elizabeth G. Gibson

  2. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA

    Rachel E. Ashley

  3. Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa College of Pharmacy, Iowa City, IA, USA

    Robert J. Kerns

  4. Departments of Biochemistry and Medicine, VA Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN, USA

    Neil Osheroff

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  1. Elizabeth G. Gibson
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  2. Rachel E. Ashley
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  3. Robert J. Kerns
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  4. Neil Osheroff
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Correspondence to Neil Osheroff .

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Editors and Affiliations

  1. Department of Medicine, University of Toronto, Toronto, ON, Canada

    I. W. Fong

  2. Anti-infectives Consulting, LLC, Stonington, CT, USA

    David Shlaes

  3. Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, USA

    Karl Drlica

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Gibson, E.G., Ashley, R.E., Kerns, R.J., Osheroff, N. (2018). Bacterial Type II Topoisomerases and Target-Mediated Drug Resistance. In: Fong, I., Shlaes, D., Drlica, K. (eds) Antimicrobial Resistance in the 21st Century. Emerging Infectious Diseases of the 21st Century. Springer, Cham. https://doi.org/10.1007/978-3-319-78538-7_16

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  • DOI: https://doi.org/10.1007/978-3-319-78538-7_16

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