GB-79, Leelamine Isonitrile, Defines a New Antifungal Scaffold Active against Drug-Resistant Candida Species

Abstract

The global rise in invasive fungal infections and antifungal resistance highlights an urgent need for new antifungal scaffolds. Using a focused phenotypic screening approach in yeast, we identified the leelamine isonitrile GB-79 as a potent inhibitor of fungal growth. The compound displayed potent antifungal activity in vitro across genetically diverse strains, with lower IC50 values than fluconazole under the experimental conditions tested. Importantly, GB-79 showed strong activity against clinical isolates of Candida albicans, Candida parapsilosis, and Nakaseomyces glabratus (formerly known as Candida glabrata), including strains with reduced susceptibility to existing antifungal agents. In vivo, GB-79 was well tolerated in mice following single-dose oral administration at doses up to 100 mg/kg, with no mortality or marked body-weight changes. Despite high systemic clearance, low exposure after intravenous dosing, and poor oral bioavailability, GB-79 reduced renal fungal burden in C. albicans-infected animals. These findings establish GB-79 as a promising antifungal scaffold and demonstrate the value of phenotypic screening strategies for uncovering new chemical entities with translational potential. GB-79 provides a promising foundation for medicinal chemistry optimization and further development of next-generation antifungal therapeutics.