Grant: Project Grant

Nonribosomal peptide synthetases (NRPSs) are large microbial enzymes that catalyze peptide bond formation. NRPSs are true macromolecular machines, huge proteins with multiple active sites, moving parts and a coordinated synthetic process. Instead of making proteins, these megaenzymes produce a vast variety of small molecules with important and diverse biological activity, such as antifungals, antivirals, antitumours, immunosuppressants, green chemicals, and (perhaps most importantly) antibacterials. The impact of NRPS products on human health has been revolutionary: Penicillin, cyclosporin, cephalosporin and daptomycin have saved tens of millions of lives worldwide. But the antibiotic resistance crisis means that even more, new and modified NRPS products are needed to help keep Canadians healthy. This research aims to expand our structural knowledge of NRPSs and the mechanisms they use to synthesize bio-active molecules. We will use chemical biology, biochemistry, biophysics and structural biology, including X-ray crystallography and cryo-electron microscopy, to characterize NRPSs and determine their three-dimensional structures at the most important steps in the process of making natural products. Then, we will use structural information to teach us how best to assemble new NRPSs, and apply a powerful kind of bioengineering which is based on making millions of variants and selecting the most active ones. This bioengineering approach should allow us to make various new NRPSs which synthesize designer next-generation drugs. The wide-ranging activities of NRPS small molecule products, combined with the potential to engineer NRPSs to produce new bio-active molecules, make them a promising source of novel therapeutics. Our studies will further our fundamental understanding of these large and complex enzymes, and show how to bioengineer them to produce tomorrow's medicines that will help us in the fight against antimicrobial resistant bacteria.