Evaluation of the Antifungal Activity of the Novel Oral Glucan Synthase Inhibitor SCY-078, Singly and in Combination, for the Treatment of Invasive Aspergillosis.

Abstract

Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin monotherapy and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed. SCY-078 is the first-in-class triterpenoid antifungal, a novel class of glucan synthase inhibitors with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species. In vitro testing of clinical strains of Aspergillus fumigatus and non-fumigatus Aspergillus strains showed that SCY-078 had potent fungistatic activity (minimum effective concentration for 90% of strains tested = 0.125 μg/ml) compared with the activities of amphotericin B (MIC90 = 8 μg/ml) and voriconazole (MIC90 = 2 μg/ml). Testing of SCY-078 in combination with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage monotherapy or combination treatment of invasive aspergillosis.

• Authors: M Ghannoum, L Long, E L Larkin, N Isham, R Sherif, K Borroto-Esoda, S Barat, D Angulo
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 62 Issue 6 (06 2018) ISSN: 1098-6596 [Electronic] United States
• PMID: 29610204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Ghannoum et al.

Chemical References

• Antifungal Agents
• Glycosides
• Nitriles
• Pyridines
• Triazoles
• Triterpenes
• isavuconazole
• Amphotericin B
• ibrexafungerp
• Glucosyltransferases
• glucan synthase
• Voriconazole

Topics

• Amphotericin B (pharmacology)
• Antifungal Agents (pharmacology)
• Aspergillus (drug effects, genetics)
• Candida (drug effects, genetics)
• Glucosyltransferases (antagonists & inhibitors)
• Glycosides (pharmacology)
• Microbial Sensitivity Tests
• Mutation
• Nitriles (pharmacology)
• Pyridines (pharmacology)
• Triazoles (pharmacology)
• Triterpenes (pharmacology)
• Voriconazole (pharmacology)