Michael G Thomas

Bacterial secondary metabolism has proven to be a rich source of natural products with medically and agriculturally relevant biological activities. Additionally, the enzymes employed by the producing organisms to generate these metabolites have proven to be a fascinating fusion of reactions that are typically seen in primary metabolism, with slight modifications to generate unusual enzymatic reactions. Thus, analysis of bacterial secondary metabolism offers the opportunity to study processes that have both basic and applied scientific interests. The overall goals of my research program are to discover, decipher, and direct bacterial secondary metabolism with these two scientific interests in mind.

Directed Evolution of Natural Product Biosynthesis Enzymes

Two of the largest classes of natural products are the nonribosomal peptides and the polyketides. The nonribosomal peptides are assembled by large protein complexes called nonribosomal peptide synthetases (NRPSs). As the name implies, NRPSs synthesize peptides independent of the ribosome. This enzymology involves a set of repeating catalytic domains that are grouped into modules. Each module contains all the catalytic domains for the incorporation and modification of one precursor (typically an amino acid) into the growing peptide chain. Nature has generated the enormous structural diversity of nonribosomal peptides by changing the number of modules, the precursors recognized and incorporated by these modules, and the modifications to the incorporated precursors. Polyketide biosynthesis works in a similar manner with repeating, modular catalytic domains controlling the incorporation of thioesterified carboxylic acids. These enzyme complexes are called polyketide synthases (PKSs) and the changing of the number of modules, precursors incorporated, and modifying domains generates enormous structural diversity in these natural products as well. While Nature has been able to generate structural diversity of nonribosomal peptides and polyketides by shuffling the NRPS and PKS domains/modules, we have not been able to fully understand what controls substrate recognition and proper protein-protein interactions in these large protein complexes to do the equivalent in a directed manner to make designer molecules. To address these issues, we have developed a set of NRPS and PKS tools that can be harnessed for directed evolution approaches to dissect NRPS and PKS enzymology. Our ultimate goal is to enable us to redirect this enzymology to generate desired molecules for drug developement.

Bioenergy Research

It is essential that we move from a petroleum-based economy to a renewable-energy based economy. The Great Lakes Bioenergy Research Center (GLBRC) is a leader in moving science towards this goal. Of particular interest to my group is adding value to the biological material remaining after a desired biofuel has been produced and extracted from the starting plant hydrolysate. This material is called conversion residue and has up to 2/3 of the carbon from the starting material. Currently this material is dried and burned to generate energy for the biorefinery. Our goal is to capture some of this carbon to produce value-added bioproducts. To do this, we are using Streptomyces species to metabolize the carbon in the conversion residue and convert it to desired bioproducts. Streptomyces species are phylogenetically and metabolically diverse and are well-known for producing secondary metabolites that are chemically similar to economically valuable bioproducts. We are using a select number of Streptomyces species as biological chassis to efficiently transform conversion residue carbon into terpene- and fatty acid-based value-added bioproducts.

Discovery of Metallophores Produced by the Human Microbiota

The acquisition of essential micronutrient transition metals (Fe, Co, Ni, Cu, Zn, Mg, and Mn) is a largely unexplored space in the commensal bacteria or microorganisms that make up the human microbiota. This area of research has been overlooked mainly due to a heavy emphasis on Fe acquisition by pathogens using metallophores called siderophores and the prevailing belief that the iron acquisition driven by the endogenous production of siderophores is not needed by the vast majority of commensals, specifically those associated with the gut. Recently, there have been reports that siderophores have biological functions beyond Fe acquisition, and many may actually have roles in acquiring other transition metals protecting the producing strain from oxidative stress, or providing a mechanism for dealing with metal toxicity. In collaboration with Profs. Federico Rey and Tim Bugni we are mining the human microbiota for metallophores to provide insights into how the producing organism accesses or blocks the intake of these micronutrients to survive in the host, while at the same time providing insights into the coevolution of the host and commensal for metal acquisition, the evolution of metallophore structural diversity, and the development of new therapeutics.