Targeting Casein Kinases in the Fungal Pathogen Candida albicans

Fungal pathogens are a major public health burden. We previously screened a library of over 700 protein kinase inhibitors and identified compounds with potent antifungal activity in combination with the echinocandin antifungal drug caspofungin, against an echinocandin-resistant isolate of Candida albicans. My thesis aimed to validate the interaction of two of the top compounds, GW416484 and SB-400868, with their putative casein kinase targets, Yck2 and Hrr25. Genetic analysis suggested that GW461484 and related molecules targeted both Yck2 and Hrr25, whereas the SB-400868 scaffold specifically engaged with Yck2. Through use of in vitro kinase assays I confirmed that Yck2 activity is inhibited by both GW461484 and SB-400868 suggesting an important role of this family of kinases in governing echinocandin resistance. In collaboration with the Savchenko Lab, we solved the structure of C. albicans Yck2. Overall, this work reveals that targeting casein kinases may be an effective strategy to cripple drug-resistant C. albicans.M.Sc