Engineering metabolic flow for rapamycin production

DESCRIPTION (provided by applicant): Rapamycin (sirolimus) has recently been approved for clinical use in transplantation medicine and improved derivatives are already under development. Rapamycin also has potential as an anti-cancer therapeutic, therefore the market for this compound is expanding rapidly. The current problem is that the rapamycin-producing organism, Streptomyces hygroscopicus, has not been improved significantly from the wild-type level, and therefore is extremely inefficient at producing this natural product. Rapamycin is very expensive to produce, which is reflected in the high cost of therapy with this drug. We propose a straightforward rational strain improvement strategy that if successful will bring the fermentation process up to a commercially acceptable production level. The approach involves metabolic engineering of two important precursor feeding pathways. Fermalogic has recently demonstrated the success of this strategy by increasing the production of the macrolide antibiotic, erythromycin. This will be the first test of this technology for a drug other than erythromycin, and will help to establish the general applicability of the strategy for strain improvement.