In Vitro and In Vivo Efficacy of a Novel and Long-Acting Fungicidal Azole, PC1244, on Aspergillus fumigatus Infection

Antimicrob Agents Chemother. 2018 Apr 26;62(5):e01941-17. doi: 10.1128/AAC.01941-17. Print 2018 May.

Abstract

The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (n = 96) with a MIC range of 0.016 to 0.25 μg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 μg/ml), especially Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 μg/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 μg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.

Keywords: Aspergillus fumigatus; CYP51; azole; azole resistant; inhalation; triazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Animals
  • Antifungal Agents / pharmacology*
  • Aspergillosis / drug therapy*
  • Aspergillus fumigatus / drug effects*
  • Aspergillus fumigatus / isolation & purification
  • Azoles / pharmacology*
  • Candida / drug effects
  • Cryptococcus / drug effects
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytokines / blood
  • Drug Resistance, Fungal
  • Epithelial Cells / metabolism
  • Ergosterol / biosynthesis
  • Fungal Proteins / antagonists & inhibitors
  • Fungal Proteins / genetics*
  • Humans
  • Hyphae / metabolism
  • Mannans / blood
  • Mice
  • Microbial Sensitivity Tests
  • Rhizopus / drug effects
  • Triazoles / pharmacology*
  • Trichophyton / drug effects
  • Voriconazole / pharmacology

Substances

  • Antifungal Agents
  • Azoles
  • Cytokines
  • Fungal Proteins
  • Mannans
  • PC1244
  • Triazoles
  • galactomannan
  • Cytochrome P-450 Enzyme System
  • cytochrome P-450 CYP51A, Aspergillus
  • cytochrome P-450 CYP51B, Aspergillus
  • Voriconazole
  • Ergosterol