Open Competition 4 - Biotechnology

De Novo Assembly of Polyketide Synthases by Combinatorial Biosynthesis

Sponsor: Kosan Biosciences

• Project Performance Period: 8/1/2002 - 7/31/2005
• Total project (est.): $4,500,000.00
• Requested ATP funds: $2,000,000.00

Polyketides are complex natural products often found in soil bacteria. They are a rich source of antibiotics, anti-cancer agents, cholesterol-lowering drugs, and other pharmaceuticals. The market for these drugs is about $15 billion annually. Typically they are produced on "assembly lines" consisting of sets of proteins and enzymatic activities known as modules, which are directed by "gene clusters" in the host organism. The number and nature of modules can be manipulated to engineer novel compounds, but today this process is largely hit-or-miss because the rules that govern how modules productively work together are not well understood. In a three-year project, Kosan Biosciences plans to use a combinatorial, step-wise approach to identify -- and demonstrate the use of -- a comprehensive set of tools that can be used to construct almost any polyketide production line and product. Rapid genetic "morphing" and analytical techniques will be developed through the use of fast-growing bacteria engineered to construct and express polyketide products. Some 140 natural modules are known and available for use; the major challenge will be the development of rapid methods of cloning and coupling modules. Combinations of module interactions will be analyzed and the few that work well will be identified. To demonstrate the results, a specific compound will be engineered and produced that shows promise as an anti-cancer drug but until now has not been available in the quantities needed for evaluation. This and some other important polyketides can be obtained only from organisms such as deep-sea sponges that cannot be cultured, or by prohibitively costly chemical synthesis. With the new technology, scientists could design genes to produce the enzymes that make such products, and the recombinant genes could be expressed in other host organisms. ATP support is needed because investors are reluctant to fund the unconventional research approach without convincing evidence that it works. If successfully developed and commercialized, the new technology would reduce the costs and time required to develop new drugs, facilitate the production of naturally occurring polyketides, and enable the rational design and production of new "natural" pharmaceuticals. To date, about 7,000 polyketides have been identified and only about 100 have been tested in humans as potential drugs.

For project information:

Michael S. Ostrach, (510) 732-8400
ostrach@kosan.com

ATP Project Manager

Thomas Wiggins, (301) 975-5416
thomas.wiggins@nist.gov