Functional Genomic and Chemical Biology Analysis of Echinocandin Resistance in Candida albicans

Candida albicans is a leading cause of invasive fungal infections, with mortality rates of ~40%. Effective treatment is hindered by the paucity of antifungal drugs and the emergence of resistance. My research exploits genetic and chemical screening approaches to uncover new therapeutic strategies to enhance the efficacy of the newest class of antifungals, the echinocandins. By screening mutant libraries collectively covering ~45% of the C. albicans genome, I identified 16 regulators of echinocandin tolerance, nine of which also modulate resistance. I identified a new role for the CCT chaperonin complex, which I found to modulate echinocandin susceptibility through actin. By screening 736 protein kinase inhibitors, I identified seven compounds that potentiate echinocandin activity. Chemogenomic profiling highlighted Yck2 and Hrr25 as potential targets of the most potent inhibitor, GW461484A. Future chemical validation of GW461484A targets and examination of in vivo utility will further uncover its therapeutic utility in combination with echinocandins.M.Sc