Paris saponin VII exerts antifungal activity and enhances amphotericin b efficacy against candida albicans via multi-target mechanisms revealed by transcriptomic analysis.

BACKGROUND

Candida albicans, an opportunistic fungal pathogen in humans, causes infections ranging from mucosal lesions to systemic dissemination. The treatment of C. albicans infections faces challenges due to increasing drug resistance and drug toxicity, especially amphotericin B (AmB). Paris saponin VII (PSVII) is a saponin derived from traditional Chinese medicinal herbs. It has been shown to possess various biological activities, including antimicrobial effects. However, its potential activity against C. albicans has not yet been documented.

PURPOSE: To explore the antifungal activity of PSVII against C. albicans and its combined effects with amphotericin B.

METHODS

The antifungal activity of PSVII was evaluated to determine its MIC against C. albicans (including the standard strain CMCC98001 and seven clinical isolates), using the broth microdilution method. SYTOX staining was employed to visualize its fungicidal effects against both yeast and hyphal forms of C. albicans. The potential interaction between PSVII and AmB was assessed by checkerboard FICI analysis and post-exposure colony count. Biofilm architecture after PSVII treatment was visualized by confocal laser scanning microscopy (CLSM). Fungal surface morphological changes were examined using SEM. The in vivo efficacy of PSVII alone and in combination with AmB was evaluated using a Galleria mellonella infection model. Finally, RNA-seq was conducted to elucidate potential mechanisms of action of PSVII and its combination with AmB.

RESULTS

PSVII showed antifungal activity against C. albicans with MIC values of 4-8 μg/ml, effectively inhibiting both yeast and hyphal forms. Combination treatment with AmB demonstrated superior efficacy, exhibiting enhanced biofilm eradication capacity. Scanning electron microscopy revealed more severe cellular shrinkage and morphological damage in the PSVII and AmB combination group, which was further confirmed by extended Galleria mellonella survival with concomitant reduction of fungal burdens. The antifungal mechanism of PSVII potentially involves disrupting heat shock protein-mediated proteolysis pathway, suppressing virulence factor expression, and interfering with redox homeostasis. The combined effects may stem from disrupted redox homeostasis, metabolic reprogramming and disrupted protein homeostasis.

CONCLUSION

This study demonstrates PSVII's antifungal activity against C. albicans and exhibits enhanced efficacy when combined with AmB. This synergistic combination highlights therapeutic potential for treating candidiasis, primarily by leveraging PSVII's synergy to boost AmB's antifungal efficacy which may allow reduction of AmB toxicity with lower dosage through PSVII synergy.