Securing and advancing natural products from remote ecosystems to inspire biomedical innovations

Natural products have a long history of use in biomedical studies of physiological pathways but have recently declined as a proportion of small molecules entering the clinic. Among the serious challenges of natural product discovery studies is ensuring a reliable supply of products for developmental studies, the re-isolation of known and well-studied chemotypes, and mitigating undesirable toxicities. Among solutions to these problems include biological and chemical synthetic strategies for abundant supply, seeking new unstudied or understudied biodiversity as sources of natural products to reduce the re-isolation of known chemotypes, and diversification of natural product analogs to produce new compounds with modulated toxicity and enhanced drug-like properties. This project executes a deep dive into the synthetic biology and genome engineering of an important natural product chemotype that displays a unique and promising bioactivity profile. Progress in this effort will not only address our knowledge gaps in polyketide biosynthetic pathways, but inform biomedical applications of small molecules with similar bioactivity profiles. Additional natural product chemotypes will be developed from biodiversity that has had little prior exploration. These organisms include marine invertebrates from Antarctica and the deep-sea, which are largely understudied due to the difficulty of accessing and working in those environments. Metabolites discovered in these studies will be diversified through analog synthesis to fully probe their potential for biomedical utility while minimizing off target bioactivity and toxicity. Natural products and their derivatives with promising bioactivity profiles will be further studied in compound development initiatives to assess their drug-like properties. Project Number: 1R35GM164236-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: BILL BAKER | Institution: UNIVERSITY OF SOUTH FLORIDA, TAMPA, FL | Award Amount: $474,102 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MCST-G (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11329886