SBIR Phase II: A Natural Product Drug Discovery Platform Based on High-Throughput Elicitor Screening (HiTES)

The broader impact of this Small Business Innovation Research (SBIR) Phase II project stems from the identification and advancement of novel compounds with therapeutic or commercial potential from natural sources. Microbial natural products have been a traditional source of FDA-approved drugs and drug leads, but discovery efforts are hampered by the fact that 80-90% of natural products that a given microbe can produce are cryptic, meaning they are not produced under standard laboratory conditions. By turning on >90% of biosynthetic pathways and unearthing these cryptic natural products, the technology developed by this project may enable discovery of novel microbial compounds, giving researchers access to urgently needed new therapeutics while making the whole process faster and more affordable than extant methodologies. This approach has the potential to usher in a new era of drug discovery, strengthening the U.S. pharmaceutical industry and economy. New antibiotics will help to combat the alarming rise of multidrug-resistant bacteria. Other pharmaceuticals, like anticancer agents, immunosuppressants and antivirals will contribute to improved health outcomes for those with cancer, autoimmune diseases, and viral infections. Of relevance to national defense and security, this technology could be used to rapidly identify novel therapeutics and bioactive compounds against emerging pandemic diseases and potential agents of bioterrorism. The proposed project seeks to develop novel antibiotics and anticancer agents using a revolutionary drug discovery platform. While natural products are the most promising source of new drugs, conventional methods of discovery fail to unlock the full metabolomic potential of the organisms that produce them, require challenging culture conditions, and are plagued with high rates of rediscovery. Phase I demonstrated proof-of-concept for a comprehensive drug discovery pipeline focusing on cryptic microbial natural products. The platform challenges bacteria with a library of small molecules, some of which mimic the bacteria’s competitive native environment, thus activating otherwise silent biosynthetic pathways. It is flexible and allows for chemistry-first or built-in bioactivity screening as the first step in the pipeline. The focus of Phase II is to further validate molecules discovered in Phase I and demonstrate the ability of the platform to uncover compounds with suitable drug-like properties. The project will also scale up the technology to establish a large library of ~2,000 novel natural products to be screened against various indications, and expand the utility for the identification of anticancer agents. Successful completion of this project will further validate and expand the utility of the platform for drug and bioactive molecule discovery. 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.