Fungal CYP51 Inhibitors VT-1161 and VT-1129 Exhibit Strong In Vitro Activity against Candida glabrata and C. krusei Isolates Clinically Resistant to Azole and Echinocandin Antifungal Compounds

Antimicrob Agents Chemother. 2017 Feb 23;61(3):e01817-16. doi: 10.1128/AAC.01817-16. Print 2017 Mar.

Abstract

The in vitro activities of fungal CYP51 inhibitors VT-1161 and VT-1129 were determined for Candida glabrata (n = 34) and C. krusei (n = 50). C. glabrata isolates were screened for FKS gene mutations. All isolates were resistant clinically and/or in vitro to at least one standard antifungal compound. VT-1161 and VT-1129 MICs for all isolates were at least 5-fold below achievable human plasma levels for VT-1161. VT-1161 and VT-1129 are promising for the treatment of resistant C. glabrata and C. krusei infections.

Keywords: Candida glabrata; Candida krusei; antifungal susceptibility testing; resistance.

MeSH terms

  • 14-alpha Demethylase Inhibitors / pharmacology*
  • Antifungal Agents / pharmacology*
  • Azoles / pharmacology
  • Candida / drug effects*
  • Candida / genetics
  • Candida / growth & development
  • Candida / isolation & purification
  • Candida glabrata / drug effects
  • Candida glabrata / genetics
  • Candida glabrata / growth & development
  • Candida glabrata / isolation & purification
  • Candidiasis / drug therapy
  • Candidiasis / microbiology
  • Drug Resistance, Fungal / drug effects*
  • Echinocandins / pharmacology
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Gene Expression
  • Glucosyltransferases / genetics
  • Glucosyltransferases / metabolism
  • Humans
  • Microbial Sensitivity Tests
  • Mutation
  • Pyridines / pharmacology*
  • Tetrazoles / pharmacology*

Substances

  • 14-alpha Demethylase Inhibitors
  • Antifungal Agents
  • Azoles
  • Echinocandins
  • Fungal Proteins
  • Pyridines
  • Tetrazoles
  • VT-1129
  • VT-1161
  • Glucosyltransferases