The goal of this project is to improve a genome-driven, correlation-based platform to unearth and then produce new bioactive compounds from fungi. This platform and research will deliver access to a large repertoire of fungal natural products, which historically have been a great source of new medicines and tool compounds. Typical estimates have natural products and their derivatives accounting for ca. 75% of the 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 natural products have yet to be identified and put into screens. Thus, new technologies are needed and here we describe an integrated plan to systematical tap into this vast potential of fungal metabolites through genomics, metabolomics and molecular biology. In the previous funding period, we developed an untargeted approach called ‘metabologenomics’ that correlates genomic content with metabolite output to uncover new hundreds of natural products and their gene clusters from soil actinobacteria. In this competing renewal, we now propose to extend the method to 250 fungi in Aim 1, advancing the field in the process. Activities described in this proposal will reduce technical barriers by establishing optimal workflows, improving experimental methodology and refining scoring metrics to create a discovery platform with the ability to unlock the medicinal potential of natural products 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 natural product 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 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 that will provide a well-defined path to discovery of NP/BGC pairs, and exploit new molecules from diverse fungi.
|Effective start/end date
|8/5/22 → 5/31/27
- National Center for Complementary and Integrative Health (5R01AT009143-19)
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