Connecting genes to molecules: Natural product biosynthesis in lichen

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The overarching goal of my research program is to discover new natural products with broad applications by mining the genome of lichen fungi. We achieve this by linking the genes we discover in the lichen genome to the biosynthesis of small biologically active molecules. Usnic acid, one of the most prevalent natural products produced by lichen fungi, has displayed biological activity ranging from antibiotic to anticancer as well as disrupting biofilm formation. However the other natural products produced by lichen fungi have been explored to a much lesser extent. This program may lead to the discovery of the next transformative natural product, like penicillin. ***Recent Progress: We are the first group in the world to carry out a systematic examination of the biosynthetic gene clusters in lichen fungi. My research group has sequenced the genome of the lichen fungi Cladonia uncialis and annotated the gene clusters that code for natural product biosynthesis. We are the first to identify the gene cluster for usnic acid biosynthesis as well as a halogenated isocoumarin natural product. Most significantly, we have identified an additional 30 gene clusters (~240 individual genes) that also code for the biosynthesis of other novel natural products. ***Current Proposal: The current Discovery grant application describes a program of research that discover new natural products in lichen fungi. The natural products produced by non-lichen fungi have been investigated for over a century and have produced some of the most significant treatments for human disease. The beta-lactam antibiotics (penicillin) and the statin (lovastatin) cholesterol lowering drugs were both discovered in fungi. However, the discovery on new molecules in lichen fungi is limited by their slow growth and the difficulty in growing cultures. Recent advances in gene sequencing technology have enabled the pace of discovery to increase in recent years. The biosynthesis of the natural products produced by lichen fungi is an unexplored, underdeveloped area that is only now become accessible. My research group is uniquely positioned make significant breakthroughs in our understanding of lichen natural product biosynthesis. This proposal will outline how we will link the genes we have annotated in the C. uncialis genome to new molecules with biological activity. These novel molecules will serve as lead compounds for novel applications that will be of broad commercial interest. ***Our results will be of significant interest to the larger natural products community, as it will represent the first systematic linking of genes to molecules in lichen fungi. This research program will continue to position my research group as an international leader in the area of natural product biosynthesis. The training environment in my research group will encourage new collaborators to seek us out, and attract new partnerships with both local and national industry.