Discovery of new therapeutic agents from halophilic microorganisms isolated from Great Salt Lake
Environmental 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. The Great Salt Lake, also recognized as “America’s Dead Sea”, is an endorheic hypersaline lake located near the University of Utah. While seawater has an average salinity of ~3.3%, the Great Salt Lake ranges between 8-28%. Recently, our lab, in collaboration with Professor William Fenical’s group at Scripps Institution of Oceanography, started a natural products drug discovery campaign aimed at interrogating halophilic bacteria isolated from this unique environment.
Our preliminary data demonstrate that the unexplored hypersaline microorganisms of the Great Salt Lake produce metabolites containing molecular scaffolds never before observed, and their genomes contain unprecedented biosynthetic machinery. Thus, these microbes serve as an ideal resource for the discovery of natural products possessing novel scaffolds as well as the characterization of new biochemical reactions.
Elucidating the biosynthesis of natural products and reprogramming biosynthetic systems
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.
By identifying the corresponding biosynthetic clusters, we will
Interrogate the strategies that nature uses for synthesizing and installing unique functional groups responsible for the observed biological activity.
Use genetic engineering to manipulate and reprogram pathways or genes in order to generate sufficient material for downstream applications or produce new chemical entities for biological activity testing.
Understanding context-dependent expression of natural product biosynthetic clusters
Natural products are synthesized by a dedicated suite of genes and sequencing efforts have not only shown that bacteria and fungi contain a large number of genes dedicated to natural product biosynthesis, most of which lie in biosynthetic clusters, but that the total number of genes significantly outnumber the natural products isolated from these organisms. Bacteria and fungi are therefore relatively untapped resources of chemical diversity with tremendous promise of producing biologically relevant molecules. This research focus aims to exploit the metabolic potential of fungi and bacteria for the discovery and development of new therapeutic agents. However, to tap into the unknown chemical potential, we need a better understanding of how biosynthetic clusters are regulated.
Determining a natural product’s ecological role for the producing organism
Psilocybin is currently in clinical trials for its utility as an anti-anxiety and anti-depressant medication. The natural role of psilocybin is not yet known and only certain mushrooms have been reported to produce the compound, production is also dependent on the fungal growth phase. In collaboration with Professor Bryn Dentinger’s group at the University of Utah, we are studying the evolution of psilocybin biosynthetic clusters, the regulation of the biosynthetic machinery, and developing new analytical methods for detecting and quantifying the various indole-containing compounds.