Metabolomic and Biochemoinformatic Approaches For Mining Human Microbiota For Immunomodulatory Small Molecules

Abstract

The numerous benefits associated with natural products isolated from the environmental sources, including soil bacteria, plants and fungi, are long known and well appreciated. Interestingly, the immense number of microorganisms that reside within our bodies and whose cell counts greatly outnumber our own represents a potentially new and practically untapped reservoir of bioactive compounds. With the advent of next generation sequencing we are only now starting to realize the complexity and biological diversity of the human microbiome. With this ever-increasing flow of genomic information, more bioactive potential in these microbes can be identified. For instance, biosynthetic assembly lines responsible for the production of two largest classes of bioactive compounds, polyketides and nonribosomal peptides, can be readily identified within the microbial genomes, providing us with a view of their bioactive profiles. In addition to the identification of biosynthetic assembly lines, the building blocks of polyketide and nonribosomal peptide products can also be accurately predicted, given the well-understood logic of assembly line operations. Nonetheless, the identification of actual products is still lagging behind. The discovery of these bioactive molecules can be achieved, however, by establishing a unique connection between genomes and molecules. Using several concrete examples, this thesis demonstrates how both metabolomic and biochemoinformatic platforms can assist in discovery of bioactive small molecules. More specifically, investigations involving three members of the human microbiome, Streptococcus mutans, Lactobacillus plantarum and Pseudomonas aeruginosa, provide distinct examples of identification of bioactive agents and assessment of their immunomodulatory potential. Interrogating the human microbiome form the angle of small molecules is critical for evaluation of microbial effects on our cells, and ultimately our health. Studying these agents will hopefully reveal interesting principles on how microorganisms speak to human cells and how this communication could lead to therapeutic strategies or downstream mechanistic revelations.