Grant: Discovery Grants Program - Individual

This Discovery grant application describes a program of research that will discover new biologically active natural products produced by lichen fungi. These new molecules will serve as new lead compounds for the development of novel antibiotic, antifungal and anticancer therapeutics. Lichen fungi are slow growing symbiotic associations of fungi (mycobionts) and algae (photobionts) and are ubiquitous in nearly every geological niche on the planet. Lichen fungi possess the ability to produce natural products - small organic molecules with antimicrobial or cytotoxic properties. However, lichen have also have been described as an "untapped resource" in regards to the fact that there has been only a limited examination of natural product biosynthesis in lichen fungi. Advances in genome sequencing, DNA synthesis and chemical analysis technology has now provided the tools to investigate the full potential of lichen natural products. The long-term objective of this program is to "find the next penicillin" from lichen fungi. The short-term objectives of this program are to link genes in the lichen genome to molecules in the metabolome. Our recent results suggest that there are numerous gene clusters that code for as-yet undiscovered chemical structures. Similarly, chemical analysis of extracts from lichen fungi (primarily by LC-MS/MS) have suggested the presence of previously undetected metabolites in these fungi. The overarching goal of this research program is to discover new biologically active natural products and conclusively identify the gene cluster responsible for their biosynthesis. This program is split into four main objectives of metabolomics, expression of gene clusters tailoring genes and synthesis of standards. The first objective will be to use chemical analysis techniques, primarily LC-MS/MS to identify new unknown molecules produced by lichen fungi. The second objective of this project will be to use the extensive library of synthesized genes from our Joint Genomics Institute Gene Synthesis Grant to identify the function of genes that we have identified in the genome of lichen species. This will be achieved by expressing these genes in a heterologous host such as Aspergillus oryzae and identify the new metabolites present. Our third objective will be to functionally express the individual genes that code for enzymes that carry out tailoring steps. These tailoring enzymes carry out oxidations, methylations and halogenations among other steps and represent novel biocatalysts. Finally, the fourth objective will be the development of novel methodology to synthesize lichen natural products. The impact of this research program will be felt worldwide amongst the community of scientists interested in discovering new bioactive natural products from lichen fungi. This research program will serve as the foundation upon which these future discoveries are built.