Among the most fertile areas of drug discovery from natural products has been polyketides, a diverse group of about 10,000 known natural products found in soil bacteria, mainly Actinomycetes, as well as in fungi, marine microorganisms and plants. Polyketides have yielded a wide array of drugs, including antibiotics (tetracyclines, erythromycins, rifamycins), anti-fungals (amphotericin B, nystatin), cancer drugs (daunorubicin, adriamycin), immunosuppressants (FK506, rapamycin), and cholesterol lowering agents (Mevacor).

About one of every 100 polyketide molecules has yielded a drug candidate. But the natural product vein appears to be pretty well mined, and few novel natural polyketides are being discovered. The goal of Kosan Biosciences Inc. is to generate libraries of novel polyketides to provide more diversity.

Relatively few new analogs have been synthesized because of the chemical complexity of the structures. Polyketides are produced by the sequential activity of from five to 50 enzymes. The polyketide antibiotic erythromycin, for example, is produced by about 30 sequential enzyme-catalyzed reactions.

Contiguous genes

Kosan (Burlingame, Calif.) is setting out to solve that problem through use of a genetically engineered host strain of Streptomyces that lacks the gene cluster for polyketide synthesis, but retains the potential to synthesize polyketides if given the proper genetic instructions. The company also has developed plasmid vectors able to replicate polyketide synthesis genes