Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase

Katherine A. Hurley, Thiago M.A. Santos, Molly R. Fensterwald, Madhusudan Rajendran, Jared T. Moore, Edward I. Balmond, Brice J. Blahnik, Katherine C. Faulkner, Marie H. Foss, Victoria A. Heinrich, Matthew G. Lammers, Lucas C. Moore, Gregory D. Reynolds, Galen P. Shearn-Nance, Brian A. Stearns, Zi W. Yao, Jared T. Shaw, Douglas B. Weibel

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Abstract

Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs - from a library of 183 derivatives - that are potent inhibitors of DNA gyrase and are active against clinical strains of Gram-negative bacteria (Escherichia coli, Shigella flexneri, and Salmonella enterica; 3 of 10 wild-type strains tested) and Gram-positive bacteria (Bacillus spp., Enterococcus spp., Staphylococcus spp., and Streptococcus spp.; all 9 of the wild-type strains tested). E. coli strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC50s of 47-170 nM) but do not alter the enzyme's ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (gyrA and gyrB genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.

Original languageEnglish (US)
Pages (from-to)942-951
Number of pages10
JournalMedChemComm
Volume8
Issue number5
DOIs
StatePublished - 2017

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ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

Hurley, K. A., Santos, T. M. A., Fensterwald, M. R., Rajendran, M., Moore, J. T., Balmond, E. I., Blahnik, B. J., Faulkner, K. C., Foss, M. H., Heinrich, V. A., Lammers, M. G., Moore, L. C., Reynolds, G. D., Shearn-Nance, G. P., Stearns, B. A., Yao, Z. W., Shaw, J. T., & Weibel, D. B. (2017). Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase. MedChemComm, 8(5), 942-951. https://doi.org/10.1039/c7md00012j