Purine metabolism dysregulation as a multi-omics signature of fatal Candida auris infection

Candida auris is a multidrug-resistant fungal pathogen linked to global healthcare outbreaks. Its metabolic processes affecting disease severity and patient outcomes are not well understood. We conducted a multi-omics analysis of 44 clinical C. auris isolates to identify molecular signatures linked to patient survival. PCA, k-means, and hierarchical clustering identified two molecular clusters linked to patient survival. Differential analysis found 43 altered metabolites and 319 altered proteins [|Log2(Fold-Change)| ≥ 1, FDR-adjusted q < 0.05] between survivor-associated (cluster A) and non-survivor-associated (cluster B) groups. Pathway enrichment analysis revealed increased lysine biosynthesis, glycolysis/gluconeogenesis, and amino acid biosynthesis in survivor isolates, while non-survivor isolates showed enrichment in oxidative phosphorylation, proteasome function, and purine metabolism, with purine metabolism supported by both proteomic and metabolomic data. Functional validation showed cluster B isolates were more susceptible to purine metabolism inhibition, with lower minimum inhibitory concentrations for mycophenolic acid and allopurinol, increased killing in TimeKill assays, and a strong correlation between inosine monophosphate levels and inhibitor sensitivity. eQTL analysis found genotype-phenotype links between antifungal resistance genes, fungal proteins, and host hematological parameters. These findings show that metabolic reprogramming relates to clinical outcomes in C. auris infection, highlighting purine metabolism as a key pathway for further study.