The lichen secondary metabolite lichesterinic acid exhibits antibiofilm activity against fungal pathogens

Lichens are well known for producing unique secondary metabolites, some of which have been shown to exhibit medically relevant bioactivities, including antimicrobial effects. With the increasing prevalence of fungal infections and the growing resistance to commonly used antimycotics, there is an urgent need for new antifungal agents, especially for aged and/or immunocompromised individuals. In this study, we screened a collection of lichen-derived metabolites for antifungal properties in two medically relevant fungal pathogens, <i>Candida albicans</i> and <i>Nakaseomyces glabratus</i>. Several compounds exhibited inhibitory effects against planktonic cells and/or biofilm formation in at least one of these species. Notably, two related paraconic acids demonstrated the strongest activity against biofilms, structures that contribute significantly to antifungal resistance. Among them, lichesterinic acid was the most effective in disrupting pre-formed biofilms and preventing biofilm formation, key challenges in clinical mycology. Importantly, lichesterinic acid showed moderate tolerability in human cells. Furthermore, lichesterinic acid displayed antifungal efficacy in an <i>in vivo</i> model of fungal infection, supporting its potential for therapeutic development. These findings highlight lichen-derived metabolites, particularly paraconic acids, as promising candidates for new antifungal therapies targeting resistant and biofilm-associated fungal infections.