The combination of farnesol and berberine effectively inhibits Candida albicans growth and biofilm formation

Abstract The formation of Candida albicans biofilms is a key factor contributing to clinical antifungal treatment failure and multidrug resistance (MDR). Overcoming biofilm formation is an urgent priority in antifungal therapy. Here, we report a synergistic strategy utilizing farnesol (FAR) combined with berberine (BBR) to inhibit Candida albicans biofilms. FAR and BBR demonstrated significant synergistic antifungal effects against both the standard strain and clinical isolates, with a fractional inhibitory concentration index (FICI) of 0.26. The FAR-BBR combination not only effectively inhibited the pathogenic morphotransformation from yeast to hyphae but also reduced biofilm-associated metabolic activity and attached biofilm biomass by up to 66.2% and 79.5%, respectively. Transcriptomic and validation analyses suggested that the enhanced antifungal activity of FAR-BBR may be associated with altered expression of genes related to MAPK signaling, efflux pump regulation, mitochondrial function, and energy metabolism. The combination treatment was also associated with impaired mitochondrial respiratory function, altered mitochondrial membrane potential, compensatory increases in the copy numbers of mitochondrial-encoded respiratory chain genes, and transcriptomic signatures indicative of metabolic remodeling toward oxidative phosphorylation and altered protein homeostasis. These changes may contribute to the inhibition of both planktonic cell growth and biofilm formation. To our knowledge, this study is the first to report that combined treatment with FAR and BBR effectively inhibits Candida albicans biofilm formation, providing a promising in vitro strategy for overcoming fungal biofilm-associated drug resistance.