Metabolome and Transcriptome Combinatory Profiling Reveals Fluconazole Resistance Mechanisms of Trichosporon asahii and the Role of Farnesol in Fluconazole Tolerance

Trichosporon asahii is a basidiomycete yeast that is pathogenic to humans and animals, and fluconazole-resistant strains have recently increased. Farnesol secreted by fungi is a factor that causes variations in fluconazole resistance; however, few studies have explored the underlying mechanisms. Therefore, this study aims to delineate the fluconazole resistance mechanisms of T. asahii and explore farnesol’s effects on these processes. A comparative metabolome–transcriptome analysis of untreated fluconazole-sensitive (YAN), fluconazole-resistant (PB) T. asahii strains, and 25 μM farnesol-treated strains (YAN-25 and PB-25, respectively) was performed. The membrane lipid-related genes and metabolites were upregulated in the PB vs. YAN and PB-25 vs. PB comparisons. Farnesol demonstrated strain-dependent mechanisms underlying fluconazole tolerance between the YAN and PB strains, and upregulated and downregulated efflux pumps in PB-25 and YAN-25 strains, respectively. Membrane lipid-related metabolites were highly correlated with transporter-coding genes. Fluconazole resistance in T. asahii was induced by membrane lipid bio-synthesis activation. Farnesol inhibited fluconazole resistance in the sensitive strain, but enhanced resistance in the resistant strain by upregulating efflux pump genes and membrane lipids. This study offers valuable insights into the mechanisms underlying fungal drug resistance and provides guidance for future research aimed at developing more potent antifungal drugs for clinical use.