Antibiotic Gene Clusters

DESCRIPTION (provided by applicant): The global health problem of microbial antibiotic resistance continues unabated. One practical aspect of this problem is that when new more effective antibiotics are found they must be produced in large enough quantities and at reasonable prices. Most antibiotics are made through Actinomycete fermentations. Despite the wide use of these organisms, very little is known about the genes that control the level, and therefore the cost, of antibiotic production. One of the best-studied Actinomycetes is the mycelial, grampositive, Saccharopolyspora erythraea, which has been used to make erythromycin since the mid-1950's. Erythromycin is the starting material for two widely prescribed semi-synthetic derivatives, Biaxin and Zithromax. It is little known that over 30 years ago another Actinomycete, Aeromicrobium erythreum, was also discovered to produce erythromycin. A. erythreum, however, is unicellular and faster growing than Sac. erythraea and has other features that make it a favorable fermentation organism. The gene cluster for erythromycin biosynthesis in this organism is uncharacterized. We propose to revisit A. erythreum and begin by cloning and sequencing the ery gene cluster from it as a prelude to further work that will lead to commercial opportunities for strain improvement and new drug discovery. PROPOSED COMMERCIAL APPLICATION: Commercial strains for the production of the bulk pharmaceutical erythromycin are responsible for the production or material with a market value of greater than $600 million per year, world-wide (1995 figure). Any strain that is significantly superior to existing strains would therefore be of great economic value. The development of new generation erythromycin derivatives means the market for erythromycin as a chemical intermediate will continue to grow.