Artemisinins inhibit oral candidiasis caused by Candida albicans through the repression on its hyphal development

Candida albicans is the most abundant fungal species in oral cavity. As a smart opportunistic pathogen, it increases the virulence byswitching its forms from yeasts to hyphae and becomes the major pathogenic agent for oral candidiasis. However, the overuse ofcurrent clinical antifungals and lack of new types of drugs highlight the challenges in the antifungal treatments because of the drugresistance and side effects. Anti-virulence strategy is proved as a practical way to develop new types of anti-infective drugs. Here,seven artemisinins, including artemisinin, dihydroartemisinin, artemisinic acid, dihydroartemisinic acid, artesunate, artemether andarteether, were employed to target at the hyphal development, the most important virulence factor of C. albicans. Artemisininsfailed to affect the growth, but significantly inhibited the hyphal development of C. albicans, including the clinical azole resistantisolates, and reduced their damage to oral epithelial cells, while arteether showed the strongest activities. The transcriptomesuggested that arteether could affect the energy metabolism of C. albicans. Seven artemisinins were then proved to significantlyinhibit the productions of ATP and cAMP, while reduced the hyphal inhibition on RAS1 overexpression strain indicating thatartemisinins regulated the Ras1-cAMP-Efg1 pathway to inhibit the hyphal development. Importantly, arteether significantlyinhibited the fungal burden and infections with no systemic toxicity in the murine oropharyngeal candidiasis models in vivo causedby both fluconazole sensitive and resistant strains. Our results for the first time indicated that artemisinins can be potentialantifungal compounds against C. albicans infections by targeting at its hyphal development.