The Synergistic Antifungal Effect and Potential Mechanism of D-Penicillamine Combined With Fluconazole Against Candida albicans

Abstract

Over the last few decades, candidiasis has exhibited an increasing incidence worldwide, causing high mortality in immunocompromised patients. <i>Candida albicans</i> is one of the leading opportunistic fungal pathogens. However, due to the increased use of antifungal agents, resistance of <i>C. albicans</i> to conventional agents, especially fluconazole, has frequently emerged. Therefore, research on the use of combinations of current drugs to sensitize antifungal agents and overcome fungal resistance has attracted considerable attention. This study demonstrated for the first time that D-penicillamine (PCA) combined with fluconazole showed a synergistic effect against <i>C. albicans</i>. PCA combined with fluconazole not only showed synergistic effects against planktonic cells of <i>C. albicans</i>, but also showed synergistic effects against <i>C. albicans</i> biofilms formed within 12 h <i>in vitro</i>. In addition, a <i>Galleria mellonella</i> infection model was used to evaluate the <i>in vivo</i> effects of this drug combination. The results showed that the combination of the two drugs could improve the survival rate, decrease the fungal burden, and reduce the tissue invasion of <i>G. mellonella</i> larvae. Finally, we explored the potential synergistic mechanisms of the drug combination, mainly including inhibition of the morphological transformation, reduction of the intracellular calcium concentration, and the activation of metacaspase, which is closely related to cell apoptosis. These findings might provide novel insights into antifungal drug discovery and the treatment of candidiasis caused by <i>C. albicans</i>.