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Fluoroquinolone Resistance: Mechanisms, Restrictive Dosing, and Anti-Mutant Screening Strategies for New Compounds

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Antibiotic Discovery and Development

Abstract

Fluoroquinolones trap gyrase and topoisomerase IV on DNA as ternary complexes that block the movement of replication forks and transcription complexes. Studies with resistant mutants indicate that resistance is due to alterations in drug permeability, drug efflux, gyrase-protecting proteins, drug-modifying enzymes, and target topoisomerases. Emergence (acquisition) of resistance is thought to arise when fluoroquinolone concentration falls inside a range in which resistant mutant subpopulations are selectively enriched and amplified. The lower boundary of the range (mutant selection window) is approximated by the minimal inhibitory concentration (MIC) of the bulk, susceptible population. The upper boundary is the MIC of the least susceptible resistant mutant subpopulation, a value called the mutant prevention concentration (MPC). MPC varies among fluoroquinolones and pathogens; when combined with pharmacokinetics, MPC can be used to compare compounds and dosing regimens for selective amplification of mutant subpopulations. Batteries of resistant mutants can be used to identify compounds that have a very narrow selection window and are likely to restrict the emergence of resistance. While most of the concepts behind the emergence of quinolone resistance are based on chromosomal mutations, plasmid-borne resistance also occurs. Thus studies of quinolones can address most aspects of antibiotic resistance.

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Acknowledgments

We thank Diarmaid Hughes and Shajo Kunnath for critical comments on the manuscript. The work was supported by NIH grant AI073491.

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Authors and Affiliations

  1. Public Health Research Institute, New Jersey Medical School, UMDNJ, 225 Warren Street, NJ, 07103, Newark, USA

    Karl Drlica, Xilin Zhao, Muhammad Malik & Tal Salz

  2. Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA, USA

    Robert Kerns

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  1. Karl Drlica
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  2. Xilin Zhao
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Correspondence to Karl Drlica .

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    Thomas J. Dougherty

  2. Achillion Pharmaceuticals, Inc., George St. 300, New Haven, 06511, Connecticut, USA

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Drlica, K., Zhao, X., Malik, M., Salz, T., Kerns, R. (2012). Fluoroquinolone Resistance: Mechanisms, Restrictive Dosing, and Anti-Mutant Screening Strategies for New Compounds. In: Dougherty, T., Pucci, M. (eds) Antibiotic Discovery and Development. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-1400-1_14

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