Inhibitory effect of copper chelators on the budding in Candida albicans

Candida albicans exhibits a unique dimorphic behavior, allowing it to switch between unicellular budding yeast and filamentous hyphal growth. This dimorphism is crucial for its pathogenicity, influencing processes such as adhesion, invasion, immune evasion, and host response. A comprehensive understanding of the molecular mechanisms governing yeast and hyphal growth, as well as the switch between these forms, is crucial for the development of effective anticandidal therapies. In this study, we screened for small molecules that interfere with the dimorphism of C. albicans and identified the actinomycete metabolite RK-276A/SF2768 as a potent inhibitor of this process. Time-lapse microscopy revealed that SF2768 inhibited hyphal branching and lateral yeast budding during the hyphal-to-yeast transition. Interestingly, SF2768 also suppressed farnesol-induced yeast growth by inhibiting yeast bud formation. The effects of SF2768 were canceled with copper addition, and other copper chelators, such as trientine and d-penicillamine, induced similar phenotypes, indicating that the copper-chelating activity of SF2768 is crucial for its antifungal properties. Furthermore, copper ions induced both hyphal and yeast bud formation. These findings strongly suggest that copper ions play a role in Candida budding, and the copper chelators could be developed as novel antifungal agents against not only dimorphic Candida spp. but also non-dimorphic Candida spp.