Description:
Unlocking Therapeutic Cryptic Metabolites with Bioactivity-HiTESPrinceton
Docket # 20-3645
Bacteria harbor an immense reservoir of potentially new and therapeutic small molecules in the form of “cryptic” biosynthetic gene clusters. These clusters can be easily identified bioinformatically, but are at best sparingly expressed under normal laboratory growth conditions; their products are therefore not interrogated during bioactivity-guided screening exercises. An estimated 80-90% of biosynthetic loci are cryptic, meaning that routine bioactivity screens will miss the majority of microbial biosynthetic potential.
Bioactivity-HiTES is a broadly applicable technology that allows access to cryptic microbial metabolites. It causes cell-wide induction of the secondary metabolomes of bacteria and links the resulting cryptic metabolites to a desired biological activity. In proof-of-concept studies, hidden antibiotics were discovered in four bacterial actinomycete strains, which do not produce antibiotics under standard growth conditions. Follow-up studies in two cases demonstrated the production of two new antibiotics: In one case, the taylorflavins, pyrimidine antibiotics that harbor selective growth-inhibitory activity toward Gram-negative bacteria, were identified. For example, taylorflavin B shows potent minimal inhibitory concentration toward Neisseria gonorrhoeae and Acinetobacter baumanii, but not against a panel of routine Gram-positive bacteria. In the second case, the lanthipeptide cebulantin, which is specific toward Gram- negative Vibrio pathogens (e.g., Vibrio cholerae and Vibrio parahaemolyticus), but does not affect the growth of Gram-positive bacteria (e.g., Bacillus subtilis and Staphylococcus aureus), was uncovered. These compounds, taylorflavins and cebulantin, may serve as useful leads in the future. At the same time, Bioactivity-HiTES may be applied broadly to identify cryptic metabolites with the desired biological properties beyond antibiosis.
Applications
- Antibiotics Research
- Drug Discovery Research
- Increasing Titers of a Drug Candidate or Desired Natural Product
- Metabolomics and Pharmacodynamics Research
Advantages
- Access to Previously Hidden Metabolites in Bacteria
- No Genetic Procedures
- Facile, Rapid, and High-Throughput Capability
- Broadly Applicable to Any Target with High-Throughput Assay
Intellectual Property & Development Status
Patent protection is pending. Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
Publications
Bioactivity-HiTES unveils cryptic antibiotics encoded in actinomycete bacteria, Kyuho Moon, Fei Xu, Chen Zhang and Mohammad R. Seyedsayamdost, ACS Chem. Biol. 2019, 14, 767-774.
Cebulantin, a cryptic lanthipeptide antibiotic uncovered using bioactivity-coupled HiTES, Kyuho Moon, Fei Xu, and Mohammad R. Seyedsayamdost, Angew. Chem. Int. Ed. 2019, 58, 5973-5977.
The Inventors
Mohammad R. Seyedsayamdost is Associate Professor in the Departments of Chemistry and Molecular Biology at Princeton University. His research focuses on the development of novel discovery approaches for natural products and potential drug candidates from microbial sources. He received a Ph.D. in Chemistry from the Massachusetts Institute of Technology and conducted postdoctoral research at Harvard Medical School before joining Princeton.
Kyuho Moon is Assistant Professor of Pharmacy at Chonnam National University. He received a Ph.D. from Seoul National University and conducted postdoctoral work at Princeton in Prof. Seyedsayamdost’s lab, before returning to South Korea to begin his independent position.
Contact:
Cortney Cavanaugh
Princeton University Office of Technology Licensing
ccavanaugh@princeton.edu
(609) 258-7256