SBIR-STTR Award

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.

Strain improvement of industrial microorganisms is required at both the clinical testing stage and commercialization stage of drug development. Although strain improvement plays an enormous economic role in reducing the costs of pharmaceutical manufacturing, this role is generally unrecognized by the public, except during a national crisis when demand for a drug may soar. The first such crisis involved the production of penicillin during World War II. Future crises may involve drugs needed to counter bio-terrorist attacks. Unfortunately, the empirical genetic methods used for strain improvement have not substantially improved since the 1940's. Modern genetic engineering technology offers hope that newer rational methods can be developed, but more basic research is required. This research is no longer being rigorously pursued by the pharmaceutical industry. In Phase I of this project we significantly broadened our understanding of the genetics of erythromycin production by cloning and sequencing a new erythromycin gene cluster. In Phase II we are proposing to apply this new basic knowledge to the development of modern methods of strain improvement for erythromycin and other important drugs