Discovery of deguelin derivatives in combination with fluconazole against drug-resistant Candida albicans

Candida albicans , as the most prevalent opportunistic pathogenic fungus, has caused great difficulty in its clinical management. At the same time, azole resistance is emerging as their extensive usage in clinical practice. In this case, the adoption of combination therapy has become a promising therapeutic strategy. In this study, a series of deguelin (Deg) derivative were prepared and identified with in vitro antifungal activity against drug-resistant C. albicans combined with fluconazole (FLC). The combination of Deg derivative 17c and FLC exhibited the best activity, with a fractional inhibitory combination index (FICI) of 0.02. The sensitization effect of 17c + FLC was further validated by the temporal fungicidal curve analysis. In addition, 17c + FLC also demonstrated inhibitory effects on the mycelial transformation and biofilm formation of resistant C. albicans , and significantly reduced the expression of key genes related to the RAS1/cAMP/PKA cell-transduction pathway.