Mangiferin enhances the antifungal activities of caspofungin by destroying polyamine accumulation.

The incidence of fungal infections has increased continuously in recent years. Caspofungin (CAS) is one of the first-line drugs for the treatment of systemic fungal infection. However, the emerging CAS-resistant clinical isolates and high economic cost for CAS administration hamper the wide application of this drug. Thus, the combined administration of CAS with other compounds that can enhance the antifungal activity and reduce the dose of CAS has gained more and more attention. In this study, we investigated the effect of mangiferin (MG) on the antifungal activities of CAS. Our results showed that MG acted synergistically with CAS against various Candida spp., including CAS-resistant C. albicans. Moreover, MG could enhance the activity of CAS against biofilm. The in vivo synergism of MG and CAS was further confirmed in a mouse model of disseminated candidiasis. To explore the mechanisms, we found that SPE1-mediated polyamine biosynthesis pathway was involved in the fungal cell stress to caspofungin. Treatment of CAS alone could stimulate SPE1 expression and accumulation of polyamines, while combined treatment of MG and CAS inhibited SPE1 expression and destroyed polyamine accumulation, which might contribute to increased oxidative damage and cell death. These results provided a promising strategy for high efficient antifungal therapies and revealed novel mechanisms for CAS resistance.