Engineering metabolic flow for rapamycin production

描述（由申请人提供）：雷帕霉素（西罗莫司）最近被批准用于移植医学的临床应用，改进的衍生物已经在开发中。雷帕霉素还具有抗癌治疗的潜力，因此这种化合物的市场正在迅速扩大。目前的问题是，生产雷帕霉素的生物，吸湿链霉菌，还没有从野生型水平得到显著改善，因此在生产这种天然产品方面效率极低。雷帕霉素的生产非常昂贵，这反映在用这种药物治疗的高成本上。我们提出了一种简单合理的菌株改进策略，如果成功，将使发酵过程达到商业上可接受的生产水平。该方法涉及两个重要前体摄食途径的代谢工程。Fermalogic最近通过增加大环内酯类抗生素红霉素的生产，证明了这一战略的成功。这将是该技术在红霉素以外的药物上的首次试验，并将有助于确立菌株改良策略的普遍适用性。

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.