Novel Antifungal Compound Z247611722 Exhibits Antifungal Activity by Inhibiting Serine Palmitoyltransferase

The global rise in fungal infections, driven by expanding at-risk populations and growing antifungal resistance, highlights the need for new therapies. However, the current antifungal arsenal remains limited and emerging resistance reduces treatment efficacy. Through high-throughput screening of 20,000 drug-like compounds, we identified Z247611722, a novel fungicidal compound active against multiple Candida species and fluconazole-resistant isolates. Chemogenomic, metabolomic, and phenotypic analyses revealed that Z247611722 disrupts sphingolipid biosynthesis, likely by targeting the serine palmitoyltransferase. The mode of action was confirmed by experimental evolution, yielding a resistant strain with a non-synonymous mutation in the serine palmitoyltransferase encoding gene, LCB2 . Structural docking suggests that Z247611722 interferes with the PLP-binding site, distinguishing its mechanism from known inhibitors such as myriocin. Importantly, Z247611722 demonstrates in vivo efficacy in an invertebrate model of C. albicans infection. These findings validate Lcb2 as a promising target and introduce a structurally-distinct sphingolipid biosynthesis inhibitor with therapeutic potential.