Evaluation of artemisinin derivative artemether as a fluconazole potentiator through inhibition of Pdr5.

Antifungal development has gained increasing attention due to its limited armamentarium and drug resistance. Drug repurposing holds great potential in antifungal discovery. In this study, we explored the antifungal activity of artemisinin and its derivatives, dihydroartemisinin, artesunate and artemether. We identified that artemisinins can inhibit the growth of Candida albicans, and can enhance the activity of three commonly used antifungals, amphotericin B, micafungin and fluconazole (FLC), on Candida albicans growth and filamentation. Artemisinins possess stronger antifungal effect with FLC than with other antifungals. Among artemisinins, artemether exhibits the most potent antifungal activity with FLC and can recover the susceptibility of FLC-resistant clinical isolates to FLC treatment. The combinatorial antifungal activity of artemether and FLC is broad-spectrum, as it can inhibit the growth of Candida auris, Candida tropicalis, Candida parapsilosis, Saccharomyces cerevisiae and Cryptococcus neoformans. Mechanistic investigation revealed that artemether might enhance azole efficacy through disrupting the function of Pdr5, leading to intracellular accumulation of FLC. This study identified artemether as a novel FLC potentiator, providing potential therapeutic insights against fungal infection and antifungal resistance.