A small molecule inhibitor of fungal histone acetyltransferase Rtt109

The histone acetyltransferase R1109 is required for pathogenesis in several clinically important fungal species. Via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of R1109 that does not inhibit other acetyltransferase enzymes such as the yeast Gcn5 or human p300 enzymes. The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism.