Fungus-mediated biosynthesis of gold nanoparticles with synergistic antifungal activity against multidrug-resistant Candida albicans

The widespread prevalence of antifungal resistance results in the ineffective treatment of Candida-related infections since current approaches still heavily rely on antifungal drugs such as azoles. Adjuvant therapy is an alternative approach to alleviate this crisis that can re-sensitize multidrug-resistant (MDR) fungi to antifungal drugs. Herein, we report a synergistic strategy to restore antifungal activity of azoles against MDR Candida albicans (C. albicans) through nanotechnology. C. albicans-mediated biosynthetic gold nanoparticles (Ca_AuNPs) exhibit a significant potentiating effect (16–32 folds) on azoles (including fluconazole, itraconazole, and voriconazole) against MDR C. albicans. Mechanistic studies demonstrate that Ca_AuNPs can promote the intracellular accumulation of fluconazole and trigger the biochemical processes including cell structure destruction, membrane potential dissipation, intracellular ROS generation, and ATP level reduction to overcome the fungal intrinsic resistance. We demonstrate that the adjuvant therapy significantly reduces fungal viability and enhances vaginal mucosa regeneration when treating Candida vaginitis-infected mice. This study reveals the potential of biosynthetic nanoparticles as novel adjuvants to extend the lifespan of existing antifungal drugs for the treatment of MDR pathogen-induced infections.