Antifungal activity of ribavirin used alone or in combination with fluconazole against Candida albicans is mediated by reducing virulence

Abstract The incidence of fungal infections has increased continuously in recent years, and drug resistance, especially resistance to fluconazole (FLC), has emerged. To overcome this challenge, research on the antifungal activities of non-antifungal agents has gained more attention. In this study, we determined the anti-Candida activity of ribavirin (RBV), an antiviral drug commonly used in the clinic, and found that RBV displayed potent antifungal activity when used alone or in combination with FLC in vitro and in vivo. In vitro, the MIC80 values of RBV were 2-4 μg/mL for FLC-susceptible C. albicans and 8 μg/mL for FLC-resistant C. albicans. When RBV, at the dose of 1μg/mL, was combined with FLC, significant synergistic effects were exhibited against FLC-resistant C. albicans, and the MICs of FLC decreased from > 512 μg/mL to 0.25-1 μg/mL. Synergism was also exhibited against C. albicans biofilm. In vivo, RBV plus FLC significantly improved the survival of infected Galleria mellonella larvae when compared with the FLC-treated group over a 4-day period, and attenuated the damage of FLC-resistant C. albicans to G. melonella larvae tissue. Furthermore, mechanistic studies indicated that the antifungal effects of RBV used alone or in combination with FLC might be associated with the inhibition of biofilm formation, reducing extracellular phospholipase activity and inhibiting hyphal growth, but might not be related to the promotion of FLC uptake and the inhibition of FLC efflux. These results will provide a promising direction for overcoming drug resistance, and for expanding the clinical application of existing drugs.