Associate Professor of Pharmacology and Toxicology
Natural Product Biosynthesis, Drug Discovery, Synthetic Biology, Antibiotic Resistance
Secondary metabolites are specialized small molecules produced in nature and often possess a variety of biological activities that can be used toward improving our quality of life. These molecules possess exquisite chemical diversity and are often an inspiration for the development of new pharmaceutical agents. Research in the Winter lab is focused on 1) Using marine fungi and halophilic microorganisms (bacteria and fungi) as resources for the discovery of new therapeutic agents; 2) Elucidating the biosynthetic blueprint that nature uses for assembling secondary metabolites in bacteria and fungi; and 3) Characterizing and reprogramming biosynthetic systems and expression platforms for the generation of chemical entities that are otherwise inaccessible through traditional fermentation or synthetic methods. To address these topics, we apply a multifaceted approach in our studies and implement research techniques from molecular biology, biochemistry, chemistry, microbiology, bioinformatics, genomics, structural biology, and bioengineering.
Drug Discovery and Development
As secondary metabolites continue to be an inspiration for drug discovery programs, new chemical entities and molecules possessing novel modes of action are in high demand. Biological pressures have been shown to influence the chemical diversity of natural products and microorganisms isolated from extreme environments often produce molecules not observed in their terrestrial counterparts. These microorganisms serve as an ideal resource for drug discovery efforts and for characterizing novel biosynthetic enzymes. In 2017, we started to explore the natural product potential of microorganisms isolated from the hypersaline environment of Great Salt Lake. Our preliminary data has demonstrated that Great Salt Lake microorganisms are a completely underexplored resource possessing significant antimicrobial activity against Gram-negative and Gram-positive bacteria and can produce natural products with unprecedented chemical modifications.
Increased concentrations of heavy metals such as lead, arsenic, selenium and mercury are also found in Great Salt Lake. These concentrations are considered toxic to humans,but microorganisms of Great Salt Lake survive and thrive under these harsh conditions. In addition to screening our unique Great Salt Lake library for the discovery of antibiotic agents, we are also comparing the genomes of all sequenced Great Salt Lake microorganisms to those sequenced from the marine environment, fresh water, and well-characterized terrestrial strains in order to identify new genes and/or pathways that have evolved for heavy metal resistance. We hope that our findings will provide new bioremediation strategies.
Characterizing Biosynthetic Systems and Enhancing Omics-Guided Natural Product Discovery
In the in the post-genomic era, the emphasis in natural product drug discovery is associated with prioritizing strains with the potential to synthesize new molecular scaffolds and avoid the re-discovery of known compounds. In bacteria, fungi, some plants and some animals, the genes encoding the biosynthetic machinery used to synthesize natural products are clustered together in the chromosome. Thus, by correlating genetic information to protein function, chemical logic can be used to connect a known metabolite to its respective biosynthetic cluster, as well as predict physico-chemical properties or molecular structures of an unknown metabolite. The development of bioinformatics platforms such as antiSMASH has streamlined the discovery process by providing detailed annotations of biosynthetic gene clusters. However, the predictions are based on previously characterized pathways, and the characterization of increasingly diverse gene clusters or cryptic clusters is needed to improve in silico prediction of natural products and expedite the discovery of unique chemistry. Under this umbrella project, we have three main objectives 1) Use bioinformatics and homology models to aid in natural product structure elucidation; 2) Identify and characterize the biosynthetic clusters associated with bioactive molecules isolated from marine fungi or our Great Salt Lake microorganisms, and 3) Apply the knowledge gleaned from the characterization of gene clusters to help prioritize strains for downstream fermentation or synthetic biology experiments.
Reprogramming Biosynthetic Systems for the Generation of New Chemical Entities
In their host organisms, secondary metabolites are assembled and modified by specialized machinery. Often times, the complex structures or chemical modifications instated by these molecular assembly lines are difficult to replicate using traditional synthetic methods, which pose significant challenges when developing pharmaceutical agents or derivatives for testing in biological assays. We aim to develop alternative approaches for producing these otherwise inaccessible molecules or derivatives by 1) Reprogramming the biosynthetic machinery for the production of therapeutic agents with increased biological activities and 2) Develop the individual enzymes that carry out complicated reactions into renewable and environmentally friendly biocatalysts for the chemoenzymatic synthesis or derivatization of new chemical entities.
References (Selected Publications)
(*= co-first author and + = co-corresponding)
- Bring Horvath, E. R.; Brazelton, W. J.; Kim, M-C.; Cullum, R.; Fenical, W.; Winter, J. M.(2023) Bacterial Diversity and the Chemical Ecology of Natural Product Producing Bacteria from Great Salt Lake. Under Review.
- Kim, M-C.; Winter, J. M.;+ Cullum, R.; Smith, A. Fenical, W.+ (2023) Bioinformatic Analysis Aids in Assigning the Stereostructures of Marinolides A and B, 24- and 26-Membered Macrolactones from a Chemically Exceptional Marine-Derived Bacterium. Marine Drugs. 21, 367.
- Terlouw, B. R.;* Blin, K.;* et al. (2022) MIBiG 3.0: A Community-Driven Effort to Annotate Experimentally Validated Biosynthetic Gene Clusters. Nuc Acids Res. 51, D1, D603-D610.
- Bradshaw, A. J.; Dentinger, B.; Backman, T.; Ramírez-Cruz, V.; Forrister, D.; Winter, J. M.; Furci, G.; Stamets, P.; Guzmán-Dávalos, L. (2022) DNA Authentication and Chemical Analysis of Psilocybe Mushrooms Reveal Widespread Taxonomic Misdeterminations and Inconsistencies in Metabolites. Appl. Environ Microbiol. 88, e0149822.
- Zhang, P.;* Wu, G.;* Heard, S. C.; Niu, C.; Bell, S. A.; Li, F.; Ye, L.; Zhang, Y.; Winter, J. M. (2022) Identification and Characterization of a Cryptic Bifunctional Type I Diterpene Synthase Involved in Talaronoid Biosynthesis from a Marine-Derived Fungus. Org Lett. 24, 7037-7041.
- Wu, G.; Dentinger, B. T. M.; Nielson, J. R.; Peterson, R. T.; Winter, J. M. (2021). Emerimicins V-X, 15 Residue Peptaibols Discovered from an Acremonium sp. through Integrated Genomic and Chemical Approaches. J Nat Prod, 84, 1113-1126.
- Shang, Z.; Winter, J. M.;+ Kauffman, C. A.; Yang, I.; Fenical, W.+ (2019) Salinipeptins: Integrated Genomic and Chemical Approaches Reveal D-Amino Acid-Containing Ribosomally Synthesized and Post-Translationally Modified Peptides from a Great Salt Lake Streptomyces sp. ACS Chem Biol, 14(3), 415-425.
- Winter, J. M.; Cascio, D.; Dietrich, D.; Sato, M.; Watanabe, K.; Sawaya, M. R.; Vederas, J. C.; Tang, Y. (2015). Biochemical and Structural Basis for Controlling Chemical Modularity in Fungal Polyketide Biosynthesis. J Am Chem Soc, 137(31), 9885-9893.
- Winter, J. M.; Sato, M.; Sugimoto, S.; Chiou, G.; Garg, N. K.; Tang, Y.; Watanabe, K. (2012). Identification and Characterization of the Chaetoviridin and Chaetomugilin Gene Cluster in Chaetomium globosum Reveals Dual Functions of an Iterative Highly-Reducing Polyketide Synthase. J Am Chem Soc, 134(43), 17900-17903.
- Winter, J. M.; Moffitt, M. C.; Zazopoulos, E.; McAlpine, J. B.; Dorrestein, P. C.; Moore, B. S. (2007). Molecular Basis for Chloronium-Mediated Meroterpene Cyclization: Cloning, Sequencing, and Heterologous Expression of the Napyradiomycin Biosynthetic Gene Cluster. J Biol Chem, 282 (22), 16362-16368.