Journal article
Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones
Nucleic acids research, Vol.44(7), pp.3304-3316
03/16/2016
DOI: 10.1093/nar/gkw161
PMCID: PMC4838383
PMID: 26984528
Abstract
Fluoroquinolones form drug-topoisomerase-DNA complexes that rapidly block transcription and replication. Crystallographic and biochemical studies show that quinolone binding involves a water/metal-ion bridge between the quinolone C3-C4 keto-acid and amino acids in helix-4 of the target proteins, GyrA (gyrase) and ParC (topoisomerase IV). A recent cross-linking study revealed a second drug-binding mode in which the other end of the quinolone, the C7 ring system, interacts with GyrA. We report that addition of a dinitrophenyl (DNP) moiety to the C7 end of ciprofloxacin (Cip-DNP) reduced protection due to resistance substitutions in
Escherichia coli
GyrA helix-4, consistent with the existence of a second drug-binding mode not evident in X-ray structures of drug-topoisomerase-DNA complexes. Several other C7 aryl fluoroquinolones behaved in a similar manner with particular GyrA mutants. Treatment of
E. coli
cultures with Cip-DNP selectively enriched an uncommon variant, GyrA-A119E, a change that may impede binding of the dinitrophenyl group at or near the GyrA-GyrA interface. Collectively the data support the existence of a secondary quinolone-binding mode in which the quinolone C7 ring system interacts with GyrA; the data also identify C7 aryl derivatives as a new way to obtain fluoroquinolones that overcome existing GyrA-mediated quinolone resistance.
Details
- Title: Subtitle
- Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones
- Creators
- Muhammad Malik - Rutgers, The State University of New JerseyArkady Mustaev - Rutgers, The State University of New JerseyHeidi A. Schwanz - University of IowaGan Luan - Rutgers Biomedical and Health SciencesNirali Shah - Rutgers Biomedical and Health SciencesLisa M. Oppegard - University of MinnesotaErnane C. de Souza - University of Iowa, Division of Medicinal & Natural Products Chemistry, College of Pharmacy, Iowa City, IA 52246, USAHiroshi Hiasa - University of MinnesotaXilin Zhao - Rutgers, The State University of New JerseyRobert J. Kerns - University of IowaKarl Drlica - Rutgers, The State University of New Jersey
- Resource Type
- Journal article
- Publication Details
- Nucleic acids research, Vol.44(7), pp.3304-3316
- Publisher
- Oxford University Press
- DOI
- 10.1093/nar/gkw161
- PMID
- 26984528
- PMCID
- PMC4838383
- ISSN
- 0305-1048
- eISSN
- 1362-4962
- Language
- English
- Date published
- 03/16/2016
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365893402771
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