Inhibitory effect of Acetylshikonin on drug-resistant Candida albicans

BACKGROUND: Candida albicans (C. albicans) is among the most common opportunistic fungal pathogens and causes superficial infections and life-threatening invasive candidiasis in immunocompromised individuals. In recent years, C. albicans has become resistant to a wide range of clinical drugs, and the identification of effective antifungal drugs is an extremely urgent medical need. Acetylshikonin (ASK) is a naphthoquinone compound extracted from Lithospermum erythrorhizon that exhibits potent antibacterial activity. However, its efficacy against C. albicans and antimicrobial mechanisms, especially against drug-resistant C. albicans, are unclear. MATERIALS AND METHODS: The antifungal activity of ASK was evaluated based on minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) measured in vitro and in mouse models of vulvovaginal candidiasis and oropharyngeal candidiasis to assess its efficacy in vivo. Mechanistic investigations included assessments of cell membrane and cell wall damage, adhesion ability, oxidative stress evaluation, protein expression, and target identification (including RT‒qPCR, molecular docking, and related methods). RESULTS: The main active ingredient from Lithospermum erythrorhizon that targets C. albicans was identified as ASK. It exhibits significant activity against drug-resistant fungi both in vitro and in vivo. Moreover, ASK can reduce the adhesion of C. albicans and damage to cell membrane and cell wall and induce apoptosis-like cell death-like cell death. In addition, ASK may directly bind to Malate Synthase 1 (Mls1) and effectively downregulate its expression and inhibit the glyoxylate cycle, leading to the generation and accumulation of large amounts of ROS, and damage to DNA to achieve its antifungal effects. CONCLUSION: ASK can treatment drug-resistant C. albicans infections, its mechanism of action is related to the inhibition of Mls1.