Natural products: biosynthesis, biomimetic synthesis and mechanism of action

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Natural products have an enormous impact on all of our lives: they include, or form the basis of, many of the antibiotics, cholesterol-lowering statins, immunosuppressants, and other therapeutic agents in use today. Our research program aims to understand how these small organic compounds are made by the producing organisms, be they bacteria, fungi, or plants. Knowledge of the assembly of these metabolites in vivo aids not only in the control of pharmaceutical production, but also holds promise for creating new structures not found before in nature: these have potential as the drugs of tomorrow. Another important aspect of generating novel chemical entities as potential drugs is to explore their chemical synthesis. Our program aims to learn from the natural assembly process how to perform more effective chemistry. Thus, we have developed a novel method that allows the fatty acid and polyketide classes of natural products to be assembled in the test tube by following the same sequence of events that occurs in nature. We are developing this method for the general synthesis of polyketide structures. In another area, we are mimicking the natural formation of beta-lactone natural products; these are relatives of the penicillin antibiotics. A third aspect of natural products that is also being explored in our lab is the mode of action of these compounds. We are exploring how two classes of compound work; understanding this mechanism of action will allow the development of better drugs. One class of compound induces apoptosis, i.e. programmed cell death, an area of enormous interest in cancer chemotherapy. The other class, the beta-lactones, is being investigated as novel anti-fungal agents; there is a great need for improved anti-fungal drugs due to the development of drug-resistant fungal strains. Our collaborator at McMaster has identified a novel cellular target for attack, a promising result since resistance is rare when new cellular pathways are targeted. We are providing the natural products and analogues to inactivate this target.