METABOLIC ENGINEERING OF ANTIBIOTIC BIOSYNTHESIS

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DESCRIPTION: Metabolic engineering of antibiotic producing actinomycetes is performed routinely in the pharmaceutical industry to increase the yield and thereby reduce the cost of production of important pharmaceutical compounds, including antibiotics. This important procedure has been performed using essentially the same empirical mutate-and-screen process for the past 50 years. Recent technical advances in the molecular genetic manipulation of these commercially important microorganisms now make it possible to approach the process of metabolic engineering from a rationale design perspective. The erythromycin producing organisms, Saccharopolyspora erythrea, is an ideal system for developing this technology because erythromycin is a well-studied molecule, the organism lends itself to recombinant manipulations, and there is a need for improving the production of this compound due to the increasing number of semi- synthetic derivatives of erythromycin currently entering the market. In preliminary work, FermaLogic scientists have uncovered strong evidence for a positive regulatory gene that affects production levels of erythromycin by a factor of five and have mapped its location within a genomic region of 265 kb. This proposal describes a strategy for finding the presumed regulatory gene and using it for further rational manipulations that will lead to the eventual design of an erythromycin super-producing strain. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE