The opportunistic fungal infections are an increasing threat to humans due to the increasing number of patients with immunodeficiency, in which the most popular fungal pathogen is Candida albicans. Fluconazole (FLC) is the common drug for treating C. albicans infections, but increasing drug resistance has limited its clinical use. Currently, combination therapy is being investigated as a treatment to overcome the resistance of C. albicans. This report investigated the synergistic properties of deferoxamine (DFO) and FLC combination therapy in vitro and in vivo against drug-resistant C. albicans. The results showed that the combination of DFO and FLC had a great synergistic antifungal effect against C. albicans, an FLC-resistant strain, with a fractional inhibition concentration index (FICI) of 0.25 by the broth microdilution checkerboard assay. Furthermore, the combination of DFO and FLC significantly inhibited the activity of C. glabrata cells (approximately 30% of C. glabrata cells are azole-resistant). The time-growth curves confirmed that the combination of DFO and FLC have a potent synergistic antifungal effect. Hyphal formation assays confirmed that DFO inhibited the hyphal induction of C. albicans. In addition, the combination of DFO and FLC significantly inhibited the expression of the adhesion gene (ALS1). In vivo experiments showed that the combination of DFO and FLC significantly reduced pustules, CFU counts and inflammatory cell infiltration in skin tissue. These results suggest that the combination of DFO and FLC inhibits yeast-hyphae transformation, reduces C. albicans infectivity and resistance in vitro and in vivo, and affects Cek1 MAPK signaling. This may offer a new option for the treatment of cutaneous candidiasis.
Keywords: Candida albicans; cutaneous candidiasis; deferoxamine; drug resistance; synergistic effect.