Sinefungin, a natural nucleoside analog of S-adenosyl methionine, impairs the pathogenicity of Candida albicans

Abstract

Abstract Candida albicans, an opportunistic fungal pathogen, causes life-threatening infections in immunocompromised patients. Current antifungals are limited by toxicity, drug-drug interactions, and emerging resistance, underscoring the importance of identifying novel treatment approaches. Here, we elucidate the impact of sinefungin, an analog of S-adenosyl methionine, on the virulence of C. albicans strain SC5314 and clinical isolates. Our data indicate that sinefungin impairs pathogenic traits of C. albicans including hyphal morphogenesis, biofilm formation, adhesion to epithelial cells, and virulence towards Galleria mellonella, highlighting sinefungin as an avenue for therapeutic intervention. We determine that sinefungin particularly disturbs N6-methyladenosine (m6A) formation. Transcriptome analysis of C. albicans hyphae upon sinefungin treatment reveals an increase in transcripts related to the yeast form and decrease in those associated with hyphae formation and virulence. Collectively, our data propose sinefungin as a potent molecule against C. albicans and emphasize further exploration of post-transcriptional control mechanisms of pathogenicity for antifungal design.