New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature

Sabine Schuster, Martina Vavra, Raphael Köser, John W A Rossen, Winfried V Kern

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Inactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of E. coli RND (resistance-nodulation-cell division)-type transporters, efflux inhibitors, and AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux-bypassing drugs and provide AcrB targets with critical relevance for this purpose.

Original languageEnglish
Article numberARTN e01803-20
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number2
Early online date16-Nov-2020
DOIs
Publication statusPublished - Feb-2021

Keywords

  • gepotidacin
  • zoliflodacin
  • drug efflux
  • TolC
  • AcrB
  • YhiV (MdtF)
  • RND-type transporter
  • fluoroquinolones
  • clinical E. coli isolates
  • MULTIDRUG TRANSPORTER ACRB
  • IDENTIFICATION
  • MUTAGENESIS
  • RESIDUES
  • SPECTRUM

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