Novel Macrolide and Ketolide Antibiotic Intermediates

新型大环内酯类和酮内酯类抗生素中间体

• 批准号: 6582821
• 负责人: J. Mark Weber
• 金额: $ 26.54万
• 依托单位: FERMALOGIC, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6582821
• 关键词: Actinomycetales; Streptococcus pneumoniae; antibacterial agents; bacterial genetics; drug design /synthesis /production; fermentation; genetic manipulation; macrolide antibiotics; molecular cloning; nucleic acid sequence; thin layer chromatography; transfection /expression vector

DESCRIPTION (provided by applicant): The objective of the proposed study is to generate novel macrolide and ketolide structures that may be useful as antibiotics themselves, or as chemical intermediates in the generation of new semi-synthetic antibiotics. Macrolides are effective in the treatment of respirtory infections. The new ketolide derivatives are particularly effective against an emerging public health threat, MLSB resistance (virginiamycin-, tylosin-, streptogramins-, and erythromycin-resistant) Streptococcus. pneumoniae. The new structures will be generated by molecular biotailoring, which is an environmentally low-impact fermentation process, as opposed to chemical synthesis. The project will involve eight biotailoring enzymes, and five macrolide- or ketolide-producing bactieral host strains, in novel combinatorial arrays to create structures that have never before been produced or tested for antibiotic activity. The biotailoring enzymes have been chosen based on analogous structure-activity relationships that show them to impart biological activity to the parent molecule. In addition, a new macrolide biosynthetic gene cluster will be cloned and its gene sequenced obtained in part, to identify new biotailoring enzymes for future work in Phase II.

描述（由申请人提供）：拟议的研究的目的是生成新型的大花环和酮醇酯结构，这些结构可能作为抗生素本身有用，或者是新的半合成抗生素的化学中间体。 大环内酯类药物可有效治疗呼吸道感染。 新的酮醇衍生物对新兴的公共卫生威胁，MLSB抗性（Virginiamycin-，tylosin-，链霉菌素，链霉菌素和耐红霉素抗抗抑素）尤其有效。肺炎。 与化学合成相反，分子生物载荷是一种新结构，这是一种环境低影响的发酵过程。该项目将涉及八种生物载荷酶，以及五种新型组合阵列中的五种大花生素或酮醇生产的宿主菌株，以创建以前从未产生或测试过用于抗生素活性的结构。已经根据类似的结构 - 活性关系选择了生物尾部酶，这些关系表明它们将生物学活性赋予了父分子。此外，将克隆一个新的大花生生物合成基因簇，并部分获得其基因，以确定新的生物尾式酶，以在II期未来工作。