(228dx) Finding Diamonds in the Rough, Genome Mining of Fungi for Human Therapeutics

Natural products (NPs) are major sources for drug discovery. Due to increasing drug resistance to existing scaffolds and dwindling pipeline of new drug leads, our needs to uncover novel NPs and generate chemical diversity are becoming ever more important. Traditional NP discovery is achieved through bioactivity-guided isolation of NPs produced by microbes. With the exploding amount of genome information available for microorganisms, the direct mining of new biosynthetic gene clusters (BGCs) that can lead to new chemical structures and biological activities is a promising approach. In my thesis project, I proposed a highly efficient strategy, target-guided mining (TGM), to bridge this gap between activity-guided NP isolation and genome-guided NP discovery. I am aiming to combine my knowledge in chemistry and biology to develop new strategies to discover promising drug molecules that may benefit human health. There are three aims to be pursued: 1. Develop bioinformatics methods and TGM to identify BCGs that may produce NPs which target enzymes that are relevant in human diseases; 2. Produce the NPs encoded in the silent BCGs using synthetic biology strategies and validate the proposed enzyme targets; 3. Optimize the activities of the compounds through synthetic and biosynthetic modifications.