Antibiotic Gene Clusters

描述(申请人提供)：微生物的全球健康问题 抗生素耐药性仍然有增无减。这个问题的一个实际方面 当发现新的更有效的抗生素时，它们必须在 数量足够大，价格合理。大多数抗生素都是由 通过放线菌发酵。尽管这些生物被广泛使用， 人们对控制水平的基因知之甚少，因此 抗生素生产的成本。研究最深入的放线菌之一是 菌丝体，革兰氏阳性，糖多孢红霉菌，已被用于 S从1950年代中期开始制造红霉素。红霉素是红霉素的起始原料 用于两种广泛处方的半合成衍生品，Biaxin和Zithromax。它 鲜为人知的是，30多年前，另一种放线菌--气微菌 红霉菌也被发现能产生红霉素。然而，红曲霉， 是单细胞的，比SAC生长得更快。红假单胞菌并具有其他特征 这使它成为一种有利的发酵微生物。的基因簇 红霉素在该生物体中的生物合成尚不明确。我们建议 重访红曲霉，从克隆和测序ery基因簇开始 作为进一步工作的前奏，这将带来商业机会 用于菌种改良和新药发现。 建议的商业应用： 用于生产原料药红霉素的商业菌株为 负责市场价值超过600美元的生产或材料 全世界每年100万美元(1995年的数字)。任何显著优于 因此，现有的菌株将具有巨大的经济价值。新技术的发展 红霉素衍生物的产生意味着红霉素作为一种化学品的市场 中级市场将继续增长。

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.