Small molecules from microbes are used widely in the clinic as antibiotics, anticancer agents, immunosuppressants, and cholesterol-lowering drugs. Our lab focuses on three emerging principles that are changing our understanding of which microbes make natural products, what roles they play in the biology of their producers, and how best to discover them:
1. Small molecules from the human microbiota. Many of the most widely used human medicines come from soil and marine bacteria, including treatments for cancer, infectious disease, diabetes, and organ transplant. We have recently found that bacteria from a surprisingly underexplored niche -- the human body -- are prolific producers of drug-like small molecules. We are identifying small molecules from gut- and skin-associated bacteria, studying their biosynthetic genes, and characterizing the roles they play in human biology and disease.
2. Computational tools for small molecule discovery. We have developed a computational algorithm that identifies small-molecule-producing genes in bacterial genomes. This algorithm has identified tens of thousands of new gene clusters in the bacterial genomes sequenced to date, many of them in the human microbiome. We are developing new algorithms that organize biosynthetic genes into families and predict the chemical structure of a small molecule directly from the sequence of its biosynthetic genes. Our tools have begun to provide the first global view of the small molecules produced by bacteria, and they generate powerful predictions that guide our experimental efforts.
3. Using synthetic ecology to control microbiome metabolism. One of the most concrete contributions the microbiome makes to human biology is to synthesize dozens of metabolites, many of which accumulate in human tissues at concentrations similar to what is achieved by a drug. We are engineering gut and skin bacterial species to produce new molecules, and constructing synthetic communities whose molecular output is completely specified.