SBIR Phase I: ClueGen: a fungi-focused metabologenomics platform for natural product discovery

The broader impact of this Small Business Innovation Research (SBIR) Phase I project will be on addressing current global problems concerning disease, pollution and climate change through the development of a new biological technology platform powered by fungi. Many natural product chemicals with broad potential uses have been discovered through traditional bioprospecting methods. However, the Achilles heel for commercial development of products based on these discoveries is that many of the compounds are difficult, expensive, or impossible to produce at scale. Further, many potent biochemicals are not typically produced under laboratory conditions, and therefore remain concealed within their host genomes. By associating known and new commercially-relevant metabolites with the genes responsible for their synthesis, this platform will open new opportunities for accessing the powerful chemistry found in fungi through modern synthetic biology and genomics. The proposed project will enable discovery of biosynthetic gene clusters (BGCs) encoding bioactive metabolites from a large private collection of Ascomycetes. The mature platform will contain thousands of annotated genome sequences from this large group of relatively unstudied fungi that have high potential for producing new drugs and crop protection molecules, in addition to uncovering enzymes that can be applied to multiple industries. A set of specific targets encompassing anti-cancer molecules, insecticides, antibiotics, and novel enzymes will be used as validation guides on the route to fully developing the resources needed for novel discovery. The goals for this project are to fully annotate BGCs from 200 genomes selected from a diverse set of bioactive fungi, and design at least 15 heterologous expression constructs encoding verticillins, antimicrobials, and insecticidal compounds for a Phase 2 project. Additionally, it is anticipated that over 100 valuable enzyme candidates will be discovered for immediate value creation with customer-partners. Together, successful completion of this project will validate the tools needed for application of the platform to the remaining ~50,000 strains in the fungal library, and drive the investment needed to launch the company. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.