Structure-guided design of antibacterials that allosterically inhibit DNA gyrase

Bioorg Med Chem Lett. 2019 Jun 1;29(11):1407-1412. doi: 10.1016/j.bmcl.2019.03.029. Epub 2019 Mar 22.

Abstract

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.

Keywords: Antibacterial; Topoisomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter baumannii / drug effects*
  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cell Line
  • Crystallography, X-Ray
  • DNA Gyrase / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Escherichia coli / drug effects*
  • Humans
  • Mice
  • Mice, Knockout
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Topoisomerase II Inhibitors
  • DNA Gyrase