GLOBAL REGULATORS OF SECONDARY METABOLISM

二次代谢的全球调节因子

• 批准号: 6138719
• 负责人: ANDREW R REEVES
• 金额: $ 10万
• 依托单位: FERMALOGIC, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138719
• 关键词: Streptomyces; binding proteins; biological products; biosynthesis; erythromycin; genetic strain; microorganism metabolism; regulatory gene

Strain improvement of pharmaceutical fermentation microorganisms reduces the cost of production of antibiotics and helps to meet the growing demand for anti-infective drugs. An important class of antibiotics which have been in increasing demand are the macrolides. Erythromycin is the most extensively produced of the macrolides, and the producer of erythromycin, Saccharopolyspora erythraea, is the model system for studying macrolide biosynthesis. Standard strain improvement is based on empirical mutate-and-screen technology, however rational manipulation of global regulators of antibiotic biosynthesis in other Streptomyces systems has led to higher-yielding strains for antibiotics such as actinorhodin. Increased production was achieved directly by increasing the copy number of the global regulatory gene or introducing a mutation into a repressor of antibiotic biosynthesis. Advances in the molecular biology of Sac. erythraea make it technically feasible to rationally engineer this strain to produce higher amounts of erythromycin. In preliminary work, two global regulatory genes in Sac. erythraea, coding for an A-factor binding protein, and a Lrp/AsnC global regulatory protein have been identified. A strategy is proposed for further characterizing and manipulating these genes to determine if they are involved in the regulation of erythromycin production and can be used for rational strain improvement. PROPOSED COMMERCIAL APPLICATIONS: Commercial strains for the production of the bulk pharmaceutical erythromycin are responsible for the production of a compound with a market value of $600 million per year, world-wide (1995 figure). Any strain that is significantly superior to existing strains would therefore be of enormous economic value. The recent development of six new generation erythromycin derivatives means the market for erythromycin as a chemical intermediate will continue to grow well into the next century.

药物发酵微生物的菌种改良降低了抗生素的生产成本，有助于满足抗感染药物日益增长的需求。大环内酯类抗生素是需求量不断增加的一类重要抗生素。红霉素是大环内酯类中产量最广泛的一种，红霉素的产生菌Saccharopolyspora erythraea是研究大环内酯类生物合成的模式系统。标准的菌株改良是基于经验突变和筛选技术，然而，在其他链霉菌系统中合理操纵抗生素生物合成的全球调节因子已经导致了放线菌素等抗生素的高产菌株。通过增加全球调控基因的拷贝数或在抗生素生物合成抑制因子中引入突变，直接实现了产量的增加。Sac的分子生物学研究进展。红霉素使得合理设计这种菌株以生产更多红霉素在技术上是可行的。在前期工作中，两个全局调控基因在Sac。已经鉴定出编码a因子结合蛋白和Lrp/AsnC全局调节蛋白的赤藓。我们提出了一种进一步表征和操纵这些基因的策略，以确定它们是否参与红霉素生产的调控，并可用于合理的菌株改良。拟议的商业应用：用于生产散装药物红霉素的商业菌株负责生产世界范围内每年市场价值为6亿美元的化合物（1995年数字）。因此，任何明显优于现有菌株的菌株都具有巨大的经济价值。六种新一代红霉素衍生物的最新发展意味着红霉素作为化学中间体的市场将在下个世纪继续增长。