Fungal infections, which commonly occur in immunocompromised patients, can cause high morbidity and mortality. Antifungal agents act by disrupting the cell membrane, inhibiting nucleic acid synthesis and function, or inhibiting β-1,3-glucan synthase. Because the incidences of life-threatening fungal infections and antifungal drug resistance are continuously increasing, there is an urgent need for the development of new antifungal agents with novel mechanisms of action. Recent studies have focused on mitochondrial components as potential therapeutic drug targets, owing to their important roles in fungal viability and pathogenesis. In this review, we discuss novel antifungal drugs targeting mitochondrial components and highlight the unique fungal proteins involved in the electron transport chain, which is useful for investigating selective antifungal targets. Finally, we comprehensively summarize the efficacy and safety of lead compounds in clinical and preclinical development. Although fungus-specific proteins in the mitochondrion are involved in various processes, the majority of the antifungal agents target dysfunction of mitochondria, including mitochondrial respiration disturbance, increased intracellular ATP, reactive oxygen species generation, and others. Moreover, only a few drugs are under clinical trials, necessitating further exploration of possible targets and development of effective antifungal agents. The unique chemical structures and targets of these compounds will provide valuable hints for further exploiting new antifungals.
Keywords: antifungal agents; antifungal targets; electron transport chain; mitochondria.