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

<i>Candida albicans</i>, 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 <i>C. albicans</i> strain SC5314 and clinical isolates. Our data indicate that sinefungin impairs pathogenic traits of <i>C. albicans</i> including hyphal morphogenesis, biofilm formation, adhesion to epithelial cells, and virulence towards <i>Galleria mellonella</i>, highlighting sinefungin as an avenue for therapeutic intervention. We determine that sinefungin particularly disturbs N6-methyladenosine (m⁶A) formation. Transcriptome analysis of <i>C. albicans</i> 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 <i>C. albicans</i> and emphasize further exploration of post-transcriptional control mechanisms of pathogenicity for antifungal design.