De Novo Acquisition of Resistance to SCY-078 in Candida Glabrata Involves FKS Mutations That Both Overlap and Are Distinct From Those Conferring Echinocandin Resistance

Antimicrob Agents Chemother. 2017 Aug 24;61(9):e00833-17. doi: 10.1128/AAC.00833-17. Print 2017 Sep.

Abstract

SCY-078 is an orally active antifungal whose target is the β-(1,3)-d-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant Candida glabrata isolates following drug exposure in vitro Resistant isolates were analyzed using broth microdilution methodology and FKS sequencing. The kinetic inhibition parameter IC50 (50% inhibitory concentration) was also determined from GS complexes. The spectrum of resistance mutations found suggested a partially overlapping but independent binding site for SCY-078 relative to echinocandins on GS.

Keywords: Candida glabrata; SCY-078; resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacology*
  • Candida glabrata / drug effects*
  • Candida glabrata / genetics
  • Candidiasis / drug therapy
  • Candidiasis / microbiology
  • Drug Resistance, Fungal / drug effects*
  • Drug Resistance, Fungal / genetics
  • Echinocandins / pharmacology*
  • Fungal Proteins / genetics*
  • Glucosyltransferases / genetics
  • Glycosides / pharmacology*
  • Humans
  • Microbial Sensitivity Tests / methods
  • Mutation / drug effects*
  • Triterpenes / pharmacology*

Substances

  • Antifungal Agents
  • Echinocandins
  • Fungal Proteins
  • Glycosides
  • MK-3118
  • Triterpenes
  • Glucosyltransferases
  • 1,3-beta-glucan synthase