Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones

Muhammad Malik, Arkady Mustaev, Heidi A. Schwanz, Gan Luan, Nirali Shah, Lisa M. Oppegard, Ernane C. De Souza, Hiroshi Hiasa, Xilin Zhao, Robert J. Kerns, Karl Drlica

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3304-3316
Number of pages13
JournalNucleic acids research
Volume44
Issue number7
DOIs
StatePublished - Mar 16 2016

Bibliographical note

Funding Information:
National Institutes of Health (NIH) [AI 07341 to K.D., AI 87671 to R.J.K.]; National Institutes of Health Predoctoral Traineeship in Biotechnology [T32GM008365]; Predoctoral Fellowships from the American Foundation for Pharmaceutical Education (to H.A.S.); Coordination for the Improvement of Higher Education Personnel (CAPES), BrazilianMinistry of Education (to E.C.d.S.) and National Natural Science Foundation of China (81473251 to X.Z.). Funding for open access charge: National Institutes of Health [AI 07341].

Publisher Copyright:
© 2016 The Author(s).

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