Research
Harnessing the biosynthetic power of microorganisms
Microorganisms produce a remarkable range of structurally diverse and complex specialized metabolites. Many of these metabolites have pharmaceutically-important properties, such as antibiotic, antiparasitic, antifungal, cholesterol-lowering, immunosuppressive and anticancer activities. We are particularly interested in host-associated bacteria and how their natural products influence host health and disease. We therefore investigate the ecological role, biological target and mode of action of the molecules we uncover.
Our research also aims to understand the biochemical mechanisms by which these natural products are made in bacteria. We then use this biosynthetic knowledge to engineer microbes so that they produce novel natural product drug derivatives with improved pharmaceutical properties. In addition, we are interested in engineering beneficial host-associated bacteria for in vivo biotherapeutic applications.
Genomics-driven discovery
Advances in genome sequencing have revealed that many bacteria have a far greater potential for making natural products than previously estimated. We pursue a genomics-driven approach to search in underexplored microbial sources for interesting new natural product biosynthetic pathways that feature unusual enzymology and/or unprecedented biosynthetic mechanisms.
Microbiome biosynthetic engineering
An important part of our research is aimed at exploiting the biosynthetic power and ingenuity of bacteria. Based on our knowledge of the biosynthetic pathway and mode of action of clinically-relevant natural products, we design strategies for engineering bacteria so that they produce novel derivatives with improved activity, stability or bioavailability. We are also engineering commensal microbes that naturally reside in the human body as chassis organisms for the controlled and targeted production of natural product therapeutics.
Biosynthetic pathway elucidation
Bacteria often use intricate biosynthetic pathways to synthesize specialized metabolites. These pathways are a valuable source of enzymes that catalyze unusual and synthetically challenging reactions. We use a combination of gene deletions, chemically-synthesized substrate analogs, site-directed mutagenesis and in vitro enzymatic studies to elucidate natural product biosynthetic pathways and study the catalytic mechanisms of unusual biosynthetic enzymes. Pathways with enigmatic transformations often hold great potential for discovering new chemistry and novel biocatalytic tools.
Ecological role & mode of action
We investigate the biological activity of the natural products we uncover and we try to understand, on a fundamental level, why bacteria have evolved to produce these metabolites and what their ecological role is. In addition, we investigate the mode of action and molecular target of human microbiota-derived metabolites and antimicrobial natural products with therapeutic potential. Our research interests also include mechanisms of antimicrobial resistance.