Discover Small Molecule Inhibitors of Yeast Rtt109

The disease impact of opportunistic fungal infections has increased significantly since late last century mainly due to the increased number of immuno-compromised patients undergoing treatment for organ transplantation and cancer and those infected with HIV. Rtt109, the histone acetyltransferase that acetylates histone H3 lysine 56, is essential for S. cerevisiae cells to survive DNA damage caused by chemotherapeutic agents. Remarkably, while sequence homologs of Rtt109 are present in all fungi species, no sequence homolog of Rtt109 has been identified in humans. Therefore, Rtt109 serves as a potential target for preventing fungal infections. Together with the University of Minnesota, we are performing a large-scale small inhibitor screen to identify small molecule inhibitors that inhibit the histone acetyltransferase (HAT) activity of Rtt109. The goal is to test whether the Rtt109 inhibitors have anti-fungal activities during cancer chemotherapy. We are also collaborating with other scientists to determine the structure of the Rtt109-Vps75 complex and optimize candidate compounds, respectively. We hope that these studies will lead to a potential drug for prevention of fungal infection during cancer chemotherapy.