Enhanced Efflux Pump Expression in Candida Mutants Results in Decreased Manogepix Susceptibility

Antimicrob Agents Chemother. 2020 Apr 21;64(5):e00261-20. doi: 10.1128/AAC.00261-20. Print 2020 Apr 21.

Abstract

Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and Candida parapsilosis that resulted in decreased manogepix susceptibility. In C. albicans, a gain-of-function mutation in the transcription factor gene ZCF29 activated expression of ATP-binding cassette transporter genes CDR11 and SNQ2 In C. parapsilosis, a mitochondrial deletion activated expression of the major facilitator superfamily transporter gene MDR1.

Keywords: APX001; APX001A; GPI anchor; Gwt1; antifungal; antifungal therapy; efflux; fosmanogepix; glycosylphosphatidylinositol; manogepix.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Aminopyridines / pharmacology*
  • Antifungal Agents / pharmacology*
  • Biological Transport / genetics
  • Candida albicans / drug effects
  • Candida albicans / genetics*
  • Candida albicans / metabolism
  • Candida parapsilosis / drug effects
  • Candida parapsilosis / genetics*
  • Candida parapsilosis / metabolism
  • Drug Resistance, Fungal / genetics
  • Genome, Fungal / genetics
  • Isoxazoles / pharmacology*
  • Microbial Sensitivity Tests
  • Whole Genome Sequencing

Substances

  • APX001A
  • ATP-Binding Cassette Transporters
  • Aminopyridines
  • Antifungal Agents
  • Isoxazoles