Fluorescent Arthrocolin with fluconazole for fluconazole-resistant Candida albicans synergistic therapy by intervening with lipid metabolism and inducing ferroptosis-like necrosis

We found that arthrocolins A-C in combination with fluconazole showed extraordinary antifungal activity against fluconazole-resistant C. albicans, by inducing apopotosis and necrosis via increasing autophagy. our data revealed that fluconazole increases intracellular accumulation of arthrocolin via analysis of intracellular fluconazole and arthrocolin contents. Metabolome analysis showed arthrocolin and fluconazole resulted in the down-regulation of biosynthesis of amino acids and up-regulation of degradation of amino acids. These data demonstrated that arthrocolin and fluconazole intensively blocked the biosynthesis of amino acids and proteins, which led to fungal cell collapse. Through co-culture with 293T cells, combining arthrocolin with fluconazole were effective at reducing fungal toxicity. Intriguingly, we detected the mRNA levels of the reported genes involved in drug resistance, and all the genes displayed significant up-regulation after arthrocolin and fluconazole treatment. Among them, arthrocolin was found to interact with amino acid residues of suggesting that Cdr1p as a potential target of arthrocolin can not conduct fluconazole efflux when arthrocolin entered into cell. In summary, our results reported the novel mechanism of synergistic antifungal activity of arthrocolin with fluconazole, and contribute to expounding a new perspective for the design of new bioactive antifungal compounds with potentially better pharmacological properties.