From Genes to Molecules and Back: Expanding the Chemical Space of Microbial and Microbiome Natural Products

ABSTRACT My research has aimed at accessing a previously hidden source of natural products that are encoded in bacterial genomes, and at investigating their structures, functions, therapeutic uses, and biosynthetic pathways. We have developed new methods to turn on production of `cryptic' natural products and shown that low-dose antibiotics are especially effective at stimulating secondary

metabolism. We have explored the functions of secondary metabolites in microbial symbiotic interactions, and contributed to natural product biosynthesis by uncovering over a dozen novel and unusual metalloenzyme-catalyzed transformations, including those involved in antibiotic biogenesis. The breadth of our work has addressed the chemistry, biology, and enzymology of microbial

secondary metabolism. My vision for the next five years is a similarly holistic approach toward illuminating this generally understudied aspect of microbial physiology by applying it to the human microbiome and overall expanding the chemical space of microbial natural products. Our work will be guided by three main questions: (i) Are there cryptic metabolites in diverse genera, notably the human

microbiome and, if so, how can they be elicited? The human microbiome provides an especially intriguing source of bacteria that can play critical roles in health and disease. Because bacteria sense and respond to the world around them with small molecules, it is reasonable to expect that human microbiota are

sources of inducible, health-relevant natural products. (ii) Can biosynthesis-guided approaches be leveraged to find unusual constitutive natural products in the human microbiome? Using a new bioinformatic search protocol, we recently mapped the `universe' of ribosomal peptide natural products synthesized by radical SAM metalloenzymes, providing an unexplored expanse of microbial biocatalysis.

The reaction scope of these enzymes will shine light on the transformations that bacteria in the microbiome have at their disposal for concocting complex peptide natural products. (iii) Can we expand the chemical space of natural products through a targeted search for selenium-containing metabolites?

We have recently identified the first dedicated biosynthetic pathway for incorporation of selenium into a natural product. Genomic evidence suggests that there are many more to be discovered. Metabolite- centric and genome-guided approaches could open the door to a collection of natural products that

contain selenium. Answering these questions will chart a new path in microbial metabolism, provide insights into metabolites and virulence factors produced by human microbiota, and expand the chemical space of microbial natural products.