De novo design of Na+-activated lipopeptides with selective antifungal activity: A promising strategy for antifungal drug discovery.

In recent years, invasive fungal infections have posed a significant threat to human health, particularly due to the limited availability of effective antifungal medications. This study responds to the urgent need for powerful and selective antifungal agents by designing and synthesizing a series of lipopeptides with lipoylation at the N-terminus of the antimicrobial peptide I6. Compared to the parent peptide I6, lipopeptides exhibited selective antifungal efficacy in the presence of Na⁺. Among the variants tested, C₈-I6 emerged as the most effective, with an average effective concentration of 5.3 μM against 12 different fungal species. C₈-I6 combated fungal infections by disrupting both cytoplasmic and mitochondrial membranes, impairing the proton motive force, generating reactive oxygen species, and triggering apoptosis in fungal cells. Importantly, C₈-I6 exhibited minimal hemolysis and cytotoxicity while effectively inhibiting fungal biofilm formation. In vivo experiments further validated the safety and therapeutic potential of C₈-I6 in treating fungal skin infections. These findings underscore the significance of lipoylation in enhancing the efficacy of antimicrobial peptides, positioning C₈-I6 as a promising candidate in fighting against drug-resistant fungal infections.