Mapping and Understanding Production of Natural Products in Fungi

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Project Summary/Abstract The goal of this project is to improve a genome-driven, correlation-based platform to unearth and produce new bioactive compounds from fungi. This platform and research will deliver access to a large repertoire of fungal natural products (NPs), which historically have been a great source of new medicines and useful compounds. Typical estimates have NPs and their derivatives accounting for ca. 75% of currently used antibiotics and nearly 60% of anti-cancer drugs along with numerous antiviral, antiparasitic, antifungal, and immunosuppressive medicines. Despite their historical successes, traditional screening programs have been severely curtailed due to declining numbers of promising new candidates and lack of ready access to new compounds. At the same time, analysis of over one thousand fungal genomes suggests that tens of thousands of high-value NPs have yet to be identified and screened. Thus, new technologies are needed and here we describe an integrated plan to systematically tap into this vast potential of fungal metabolites through genomics, metabolomics, bioactivity screening and molecular biology. In the previous funding period, we developed an untargeted approach called `metabologenomics' that correlates genomic content with metabolite output to uncover hundreds of new NPs and their gene clusters from soil actinobacteria. In this competing renewal, we now propose to extend the method to 300 fungi while integrating bioactivity screening in Aim 1. Activities described in this proposal will reduce technical barriers by establishing new workflows, improving experimental methodology, and refining scoring metrics to create a discovery platform with the ability to help unlock the medicinal potential of NPs in the fungal kingdom. In Aim 2, we focus on the targeted capture and expression of BGCs in specific euchromatic loci in a widely used host for NP heterologous expression, Aspergillus nidulans. The two Aims of the project describe the generation of genomic, metabolomics, bioactivity, and expression data. We further propose to make data- and milestone-driven progress on the combination of these complementary data types to systematically examine a set of 300 fungal strains. With a proven track record of deep collaboration among the team members involved, we will deliver a robust implementation of the proposed activities to provide a well-defined path to discovery of bioactive NP/BGC pairs, and study the production of new molecules from diverse fungi.