Natural Product Discovery from a Streamline Environment-to-Bioassay Pipeline

Natural products (NPs) have long been central to drug discovery as sources of new therapeutics and drug leads. Despite major advances in microbial NP discovery over the past century, the earliest stages of the workflow—from sample collection to library generation—have remained largely unchanged. Chapter 1 reviews the history of modern antibiotic discovery with emphasis on the methodologies and strategies used to discover NPs. Chapter 2 addresses key front end limitations and introduces a semi automated Environment to Bioassay pipeline that integrates robotics, high throughput screening, and MS based bioinformatics to rapidly select, screen, and prioritize bacteria in multi well plates. This workflow enables levels of throughput and data collection not typically associated with academic NP discovery. When applied to 22 samples from a dive collection, 1049 isolates were processed in seven workdays, resulting in a curated set of 20 non redundant bioactive strains. One of these strains led to the isolation and putative characterization of surugamide analogs. The pipeline’s scalability and accessibility also enabled community-based NP discovery. Chapter 3 describes a STEM outreach program with the Boys and Girls Clubs of Chicago, where middle school students conducted hands-on biomedical research, explored STEM careers, and built mentorship connections. Post-program assessments showed increased STEM identity, engagement, and project ownership. The program also led to the discovery of a new cyclic lipodepsipeptide, orfamide N, from a P. idahonensis isolate obtained from goose feces. Chapter 4 details the isolation, structure elucidation, and biological activity of orfamide N. Finally, Chapter 5 investigates the mosquito gut bacterium S. ureilytica M01 as a source of antiviral NPs. Bioassay guided fractionation and spectroscopic analyses led to the isolation and characterization of glucosamine derivatives with activity against Chikungunya virus. Ongoing work aims to elucidate their mechanism of action and the role of S. ureilytica M01 in viral transmission. Collectively, this dissertation advances microbial NP discovery by innovating the front end of discovery workflows, demonstrating the value of university-community partnerships, and uncovering bioactive metabolites from diverse microbial sources. These findings underscore the importance of efficient front-end strategies for identifying and prioritizing promising bacterial isolates in NP based drug discovery.

Author dc:creator

• Jin Yi Tan (11009138)

• Chemistry, Analytical
• Biology, Microbiology

Statement dc:rights

• In Copyright
• Open Access after 2028-05-01

DOI dc:identifier

https://doi.org/10.25417/uic.32995262.v1

OAI identifier oai:identifier

oai:figshare.com:article/32995262