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Mangiferin enhances the antifungal activities of caspofungin by destroying polyamine accumulation
Juan Shen1, RenYi Lu2, Qing Cai1
1Shanghai Skin Disease Hospital, Tongji University School of Medicine , Shanghai, P.R. China.
Abstract:
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.
Insights
Mangiferin (MG) enhances the antifungal activity of caspofungin (CAS) against Candida species, including resistant strains and biofilms. This combination therapy may overcome caspofungin resistance by disrupting fungal polyamine biosynthesis.
Area of Science:
- Mycology
- Pharmacology
- Biochemistry
Background:
- Rising incidence of fungal infections necessitates new therapeutic strategies.
- Caspofungin (CAS) resistance and high cost limit its clinical application.
- Combined therapies with CAS are explored to enhance efficacy and reduce dosage.
Purpose of the Study:
- To investigate the synergistic effect of mangiferin (MG) with CAS against fungal infections.
- To evaluate MG's potential to overcome CAS resistance and enhance anti-biofilm activity.
- To elucidate the underlying mechanisms of MG-CAS synergy.
Main Methods:
- In vitro testing against various Candida species, including CAS-resistant strains.
- Biofilm inhibition assays.
- In vivo studies using a mouse model of disseminated candidiasis.
- Analysis of the SPE1-mediated polyamine biosynthesis pathway.
Main Results:
- MG demonstrated synergistic activity with CAS against Candida spp., including CAS-resistant isolates.
- MG enhanced CAS efficacy against fungal biofilms.
- Synergism was confirmed in a murine candidiasis model.
- MG-CAS combination inhibited SPE1 expression and polyamine accumulation, increasing oxidative damage.
Conclusions:
- Mangiferin acts synergistically with caspofungin, offering a promising strategy against fungal infections.
- This combination overcomes caspofungin resistance, potentially by targeting the polyamine biosynthesis pathway.
- The findings provide insights into novel mechanisms of caspofungin resistance.
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