Candida albicans is the most abundant fungal species in oral cavity. As a smart opportunistic pathogen, it increases the virulence by switching its forms from yeasts to hyphae and becomes the major pathogenic agent for oral candidiasis. However, the overuse of current clinical antifungals and lack of new types of drugs highlight the challenges in the antifungal treatments because of the drug resistance 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 and arteether, were employed to target at the hyphal development, the most important virulence factor of C. albicans. Artemisinins failed to affect the growth, but significantly inhibited the hyphal development of C. albicans, including the clinical azole resistant isolates, and reduced their damage to oral epithelial cells, while arteether showed the strongest activities. The transcriptome suggested that arteether could affect the energy metabolism of C. albicans. Seven artemisinins were then proved to significantly inhibit the productions of ATP and cAMP, while reduced the hyphal inhibition on RAS1 overexpression strain indicating that artemisinins regulated the Ras1-cAMP-Efg1 pathway to inhibit the hyphal development. Importantly, arteether significantly inhibited the fungal burden and infections with no systemic toxicity in the murine oropharyngeal candidiasis models in vivo caused by both fluconazole sensitive and resistant strains. Our results for the first time indicated that artemisinins can be potential antifungal compounds against C. albicans infections by targeting at its hyphal development.

白色念珠菌是口腔中最丰富的真菌种类。作为一种聪明的机会致病菌，它通过将其形式从酵母转变为菌丝来增加毒力，成为口腔念珠菌病的主要病原体。然而，目前临床抗真菌药物的过度使用和新型药物的缺乏，由于耐药性和副作用，凸显了抗真菌治疗的挑战。抗毒力策略被证明是开发新型抗感染药物的切实可行的方法。在此，采用了七种青蒿素，包括青蒿素、二氢青蒿素、青蒿酸、二氢青蒿酸、青蒿琥酯、蒿甲醚和蒿乙醚，用于靶向白色念珠菌最重要的毒力因子——菌丝发育。青蒿素未能影响白色念珠菌的生长，但显着抑制白色念珠菌（包括临床唑类耐药菌株）的菌丝发育，并减少其对口腔上皮细胞的损伤，而青蒿乙醚表现出最强的活性。转录组结果表明，蒿甲醚可以影响白色念珠菌的能量代谢。随后证明7种青蒿素能够显着抑制ATP和cAMP的产生，同时降低对RAS1过表达菌株的菌丝抑制，表明青蒿素通过调节Ras1-cAMP-Efg1途径来抑制菌丝发育。重要的是，在体内由氟康唑敏感和耐药菌株引起的小鼠口咽部念珠菌病模型中，蒿甲醚显着抑制真菌负荷和感染，且无全身毒性。我们的结果首次表明，青蒿素可以通过针对白色念珠菌菌丝发育而成为对抗白色念珠菌感染的潜在抗真菌化合物。