Mechanisms in RiPP Natural Product Biosynthesis

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Natural products are chemical compounds made by living organisms that serve numerous biological, ecological, and anthropological functions most notably as medicines to treat a variety of human illnesses. Indeed, the majority of all drugs approved for human use by the US Food and Drug Administration are either natural products or are synthetic derivatives of natural products, clearly underscoring the importance of these molecules to the quality of human life in the 21st century. In recent years, however, many of the natural products that have been traditionally used to treat human bacterial infections have lost their effectiveness due to the widespread emergence of antimicrobial resistance. In light of this daunting threat, renewed efforts in discovering and developing novel antimicrobial natural products are urgently needed. The proposed research program seeks to address this growing crisis through several distinct, but cohesive research directions that aim to illuminate the mechanistic principles of the enzymes that construct natural products. Initial studies will be focused on developing several emerging biophysical methods to characterize biosynthetic enzymes from unique perspectives. These studies will provide a molecular mechanistic understanding of what enables biosynthetic enzymes to perform their functions, and will provide insights into how those functions may potentially be manipulated for synthetic purposes. In addition, the program will identify and characterize molecules with unusual structures and enzymes with unusual functions, as potential avenues for identifying new antimicrobial compounds and new tools for the structural modification of compounds, respectively. Altogether, understanding*natural product biosynthesis on a molecular mechanistic level provides a*critical foundation for guiding the characterization of new natural products, for the rational*engineering of structures that do not exist in nature, a-nd for the targeted production of molecules of interest. As such, the proposed research program is expected to greatly benefit the ongoing and mounting struggle to combat drug resistant human pathogens - an endeavor of immense importance to the people of Canada and across the world.