Silver nanoparticles offer a synergistic effect with fluconazole against fluconazole-resistant Candida albicans by abrogating drug efflux pumps and increasing endogenous ROS

Objectives A frequent emergence of drug resistance has been observed and posed great threat to global public health recently. This work aimed to investigate the potential synergistic effect and the underlying mechanisms of AgNPs-fluconazole combination more extensively through 2 clinically isolated fluconazole-resistant Candida albicans ( C. albicans ) strains. Methods Antifungal properties of AgNPs and fluconazole alone or together against planktonic cells and biofilms were tested. Cellular and molecular targets associated with fluconazole resistance were monitored after AgNPs treatment. Antifungal potential of AgNPs-fluconazole combination was also explored in vivo using a mouse model of disseminated candidiasis. Tissue burden and survival rate were analyzed. Results The results indicated that AgNPs worked synergistically with fluconazole against both planktonic cells of fluconazole-resistant C. albicans and biofilms formed <12 h. AgNPs treatment down-regulated ERG1 , ERG11 , ERG25 , and CDR2 , decreased membrane ergosterol levels and membrane fluidity, reduced membrane content of Cdr1p, Cdr2p, and thus efflux bump activity. The elevated ROS production was also a likely cause of the synergistic effect. In vivo , AgNPs and fluconazole combination significantly decreased the fungal burden and improved the survival rate of infected mice. Conclusion In conclusion, these results further confirm that AgNPs-fluconazole combination is a hopeful strategy for the treatment of fluconazole-resistant fungal infections.