The novel second-generation triterpenoid SCY-247 maintains in vitro and in vivo activity against resistant Candida glabrata

Abstract

Candida glabrata is a major cause of invasive candidiasis and is considered a high-priority fungal pathogen by the World Health Organization. SCY-247 is a second-generation IV/oral triterpenoid antifungal that targets the fungal cell wall by inhibiting glucan synthase. We evaluated the in vitro activity and in vivo efficacy of SCY-247 against echinocandin-resistant C. glabrata. Susceptibility testing was performed against 34 C. glabrata clinical strains, including 29 echinocandin non-susceptible or resistant strains, by the CLSI broth microdilution method. Neutropenic mice were infected intravenously with either an echinocandin-susceptible or resistant strain. Treatment with vehicle control, SCY-247 (16, 32, and 48 mg/kg PO BID), fluconazole (20 mg/kg PO QD), or caspofungin (5 mg/kg IP QD) was initiated 24 hours post-inoculation. Treatment continued for 7 days, and kidney and lung tissues were collected on day 8 for analysis of fungal burden. SCY-247 maintained in vitro activity against 24 of the 29 echinocandin non-susceptible/resistant strains; SCY-247 was also efficacious against echinocandin-susceptible and resistant C. glabrata invasive candidiasis. Dose-dependent reductions in kidney and lung fungal burdens were observed in mice treated with SCY-247. In contrast, neither fluconazole nor caspofungin led to reductions in fungal burden in mice infected with the resistant strain. SCY-247 concentrations measured 12 hours after the last dose increased in a dose-dependent fashion, and those within the kidneys and lungs were markedly higher than the SCY-247 MIC90 value calculated against all strains tested. These data support the potential utility of SCY-247 therapy against invasive infections caused by resistant C. glabrata.