Synergic effect of deferoxamine combined with fluconazole against fluconazole-resistant Candida Spp. through inhibited Cek1 MAPK signaling pathway

Abstract Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM Objectives The opportunistic fungal infections represent an increasing threat to humans with the increase of immunocompromised patients, in which Candida albicans is the most common fungal pathogen. Though fluconazole (FCA) is still the first line choice to treat C. albicans infections, several limitations such as an increase in drug resistance compromised its clinical application. This study proposes a combination therapy of deferoxamine (DFO) and FCA to overcome C. albicans resistance. Methods Checkerboard microdilution assay was used to determine the minimum inhibitory concentration (MIC) of DFO used alone and in combination with FCA against FCA-resistant Candida Spp. Spot assay and time-kill curves were used to investigate the cell viability and dynamic inhibitory effect. Hyphal formation was performed to investigate the underlying mechanism of DFO. Then, a murine model of cutaneous candidiasis was established to explore the in vivo synergistic activity of DFO and FCA. Results DFO combined with FCA showed synergistic antifungal activity against FCA-resistant C. albicans, with a fractional inhibitory concentration index (FICI) of 0.25. Moreover, DFO combined with FCA significantly inhibited the activity of C. glabrata cells, which is naturally insensitive to antifungal drugs. The spot assay and time-kill curve assay indicated that DFO can turn the fungistasis activity of FCA into fungicidal activity. Hyphal formation study showed the inhibition of hyphal induction of C. albicans. DFO combined with FCA also significantly inhibited the expression of Cek1 MAPK signaling pathway-related genes (CEK1 and CPH1) and adhesion-related genes (ALS1). In vivo data showed DFO combined with FCA significantly reduced the pustule, CFU numbers, and inflammatory cell infiltration of skin tissue. Conclusion Our results suggest that DFO combined with FCA inhibited the transformation of yeast-hyphae through Cek1 MAPK signaling pathway, resulting in reduced infectivity and resistance of C. albicans in vitro and in vivo, which may provide a new option for the treatment of cutaneous candidiasis.