S66: Synthetic biology and the natural products drug discovery revolution

Many of the pharmaceuticals in wide use today such as cyclosporine and lovastatin are natural products synthesized by particular bacteria or fungi.   These drugs are synthesized biologically by stepwise assembly of standard amino acids, nonstandard amino acids, acetates, propionates, or butyrates on modular enzymes referred to as peptide synthetases or polyketides synthases.  Though there has been considerable interest in harnessing these enzymes to create a reliable system for the design and production of new natural products that can be developed as drugs, a robust system for the rapid design and synthesis of new natural products has not emerged.  A major bottleneck has been the lack of high throughput genomic-engineering methods that enable the rapid design and production of engineered microorganisms that synthesize specific new natural products.  Modular Genetics, Inc. has developed an automated system for microbial engineering that surmounts this bottleneck.   We will describe the use of this system to generate and test hundreds of engineered microorganisms.  Significantly, we will demonstrate that this approach enables the rapid reprogramming of peptide synthetase specificity, leading to the efficient bio-synthesis of new natural products that can be developed as drugs.  This approach should be particularly useful for the discovery of new therapeutics for treatment of disease in the developing world since bio-production of therapeutics via fermentation can be performed at a low cost, thus controlling the cost of goods.  Furthermore, this approach enables “green” production of drugs via the use of fermentation to convert simple renewable raw materials into complex biologically active compounds.