ERYTHROMYCIN ANALOGS BY METABOLIC ENGINEERING

描述(改编自申请)：新的分子遗传学 现在正在使用各种方法来产生抗生素结构，这种结构可以 不能通过化学合成具有成本效益地生产。新的 “组合生物合成”方法与分子生物学 “代谢工程”使用放线菌分子的特殊工具 遗传学和不断增长的克隆和测序抗生素集合 生物合成途径基因。已经创建了许多结构 和至少一种定制结构6-脱氧红霉素，已经 与母体化合物相比，生产的性能更好。这个 申请者提议扩大潜在的新结构的数量， 可以通过开发新的基因转移系统来创造 使其他14元环大环内酯类抗生素类似的微生物 红霉素。他们提议克隆现有的新的同源物 “剪裁”酶并使其失活以产生新的结构 改善的化学或生物活性，可能导致 开发新的化学中间体，可能还有新的抗生素。 建议的商业应用： 我们提议创造14元大环内酯的新类似物 具有潜在治疗价值的抗生素将作为新的有用的 化学中间体或新的人类或兽医疗法。这个 大环内酯类抗生素的市场规模达数亿美元 美元，而且还在不断增长。我们的商业潜力 新的结构意义重大。

DESCRIPTION (Adapted from the application): Novel molecular genetic methods are now being used to generate antibiotic structures that could not be cost-effectively produced through chemical synthesis. The new methods of "combinatorial biosynthesis" and molecular biological "metabolic engineering" use the special tools of Actinomycete molecular genetics and the growing collection of cloned and sequenced antibiotic biosynthetic pathway genes. Already, many structures have been created and at least one tailored structure 6-deoxyerythromycin, has been produced with improved properties over the parent compound. The applicant proposes to expand the potential number of new structures that can be created through the development of new gene transfer systems in organisms that make other 14-member ring macrolide antibiotics similar to erythromycin. They propose to clone new homologs of existing "tailoring" enzymes and inactivate them to generate new structures with improved chemical or biological activity that could lead to the development of new chemical intermediates and possibly new antibiotics. PROPOSED COMMERCIAL APPLICATION: We are proposing to create novel analogs of 14-membered macrolide antibiotics with potential therapeutic value that will be useful as new chemical intermediates or new human or veterinary therapeutics. The market for macrolide antibiotics is in the hundreds of millions of dollars per year and is still growing. The commercial potential for our new structures is significant.