The C7-aminomethylpyrrolidine group rescues the activity of a thio-fluoroquinolone

Sarah R.C. Lentz, Pratik R. Chheda, Lisa M. Oppegard, Tyrell R. Towle, Robert J. Kerns, Hiroshi Hiasa

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

A Mg 2+ -water bridge between the C-3, C-4 diketo moiety of fluoroquinolones and the conserved amino acid residues in the GyrA/ParC subunit is critical for the binding of a fluoroquinolone to a topoisomerase-DNA covalent complex. The fluoroquinolone UING-5-249 (249) can bind to the GyrB subunit through its C7-aminomethylpyrrolidine group. This interaction is responsible for enhanced activities of 249 against the wild type and quinolone-resistant mutant topoisomerases. To further evaluate the effects of the 249-GyrB interaction on fluoroquinolone activity, we examined the activities of decarboxy- and thio-249 against DNA gyrase and conducted docking studies using the structure of a gyrase-ciprofloxacin-DNA ternary complex. We found that the 249-GyrB interaction rescued the activity of thio-249 but not that of decarboxy-249. A C7-group that binds more strongly to the GyrB subunit may allow for modifications at the C-4 position, leading to a novel compound that is active against the wild type and quinolone-resistant pathogens.

Original languageEnglish (US)
Pages (from-to)24-27
Number of pages4
JournalBiochimie
Volume160
DOIs
StatePublished - May 2019

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (NIH) grant R01 AI087671 (to RJK). PRC acknowledges support of the NIH Predoctoral Training Program in Biotechnology ( GM008365 ) and the University of Iowa Center for Biocatalysis and Bioprocessing fellowship. TRT acknowledges support of the NIH Predoctoral Training Program in Pharmacological Sciences ( GM067795 ), the American Foundation for Pharmaceutical Education Predoctoral Fellowship Program, and the American Chemical Society Division of Medicinal Chemistry Fellowship sponsored by Richard B. Silverman.

Publisher Copyright:
© 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)

Keywords

  • DNA gyrase
  • Drug design
  • Fluoroquinolone
  • Quinolone resistance
  • Topoisomerase

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