Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel "unnatural" natural products

The structures of complex polyketide natural products, such as erythromycin , are programmed by multifunctional polyketide synhases (PKSs) that contain modular arrangements of functional domains. The colinearity between the ac tivities of modular PKS domains and structure of the polyketide product por tends the generation of novel organic compounds-"unnatural" natural product s-by genetic manipulation. We have engineered the erythromycin polyketide s ynthase genes to effect combinatorial alterations of catalytic activities i n the biosynthetic pathway, generating a library of >50 macrolides that wou ld be impractical to produce by chemical methods. The library includes exam ples of analogs with one, two, and three altered carbon centers of the poly ketide products. The manipulation of multiple biosynthetic steps in a PKS i s an important milestone toward the goal of producing large libraries of un natural natural products for biological and pharmaceutical applications.