Novel Macrolide and Ketolide Antibiotic Intermediates

描述（由申请人提供）：拟议研究的目的是生成新的大环内酯和酮内酯结构，这些结构本身可能用作抗生素，或作为生成新的半合成抗生素的化学中间体。大环内酯类药物治疗呼吸道感染有效。新的酮内酯衍生物对新出现的公共卫生威胁，MLSB耐药（维吉尼亚霉素、泰洛菌素、链霉素和红霉素耐药）链球菌特别有效。肺炎。新的结构将通过分子生物剪裁产生，这是一种环境低影响的发酵过程，而不是化学合成。该项目将涉及8种生物剪裁酶和5种产生大环内酯或酮内酯的细菌宿主菌株，以新颖的组合阵列来创建以前从未生产或测试过抗生素活性的结构。生物裁剪酶的选择是基于类似的结构-活性关系，表明它们赋予母体分子生物活性。此外，我们还将克隆一个新的大环内酯生物合成基因簇，并对其进行部分测序，以确定新的生物剪裁酶，为今后的二期工作提供依据。

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.