MOLECULAR BIOTAILORING OF MACROLIDE ANTIBIOTICS

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Novel molecular genetic methods are now being used to generate antibiotic structures that could not be cost-effectively produced through chemical synthesis. The new methods of "combinatorial biosynthesis" and molecular biological "tailoring" use the special tools of Actinomycete molecular genetics and the growing collection of cloned and sequenced antibiotic biosynthetic pathway genes. Already, many novel structures have been created and at least one tailored structure, 6-deoxyerythromycin, has been produced with improved properties over the parent compound. We propose to expand the potential number of new structures that can be created through the development of new gene transfer systems in organisms that make other 14-member ring macrolide antibiotics similar to erythromycin. We propose to clone new homologs of existing "tailoring" enzymes and study the substrate specificity of these enzymes in vivo. These experiments may lead to the generation of new structures with improved chemical or biological activity that could lead to the development of new chemical intermediates and quite possibly, new antibiotics. PROPOSED COMMERCIAL APPLICATION Macrolide antibiotics are a class of polyketides which include powerful antibiotics, immunosuppressants and anticancer agents which together account for sales of about $5 billion a year. The market for bulk erythromycin as a chemical intermediate is in the hundreds of millions of dollars per year. We are proposing to create novel structures that will be useful as chemical intermediates or new therapeutics in this class of molecules with known therapeutic value. The commercial potential is enormous.