The Chemoglycorandomization of Natural Products

描述（由申请人提供）：万古霉素的碳水化合物修饰类似物是克服细菌对这种最后防线抗生素耐药性的非常有希望的先导药物。不幸的是，很少有方法可用于改变天然产物碳水化合物配体。这种限制使得结构-活性关系难以建立，并减缓了药物发现的步伐。我们建议开发组合生物合成方法，以创建新的碳水化合物衍生的天然产物类似物，并进一步多样化这些产品使用化学选择性连接。使用所描述的串联组合生物合成/化学选择性连接方法，我们将产生化合物文库，以及产生万古霉素/膜活性抗生素嵌合体。该研究将有可能产生新的药物先导化合物并阐明构效关系。

DESCRIPTION (provided by applicant): Carbohydrate-modified analogs of vancomycin are highly promising leads for overcoming bacterial resistance to this last-line-of-defense antibiotic. Unfortunately, there are few methodologies available to alter natural product carbohydrate ligands. This limitation makes structure-activity relationships difficult to establish and slows the pace of drug discovery. We propose to develop combinatorial biosynthesis methodology to create novel carbohydrate-derivatized natural product analogs, and further diversify these products using chemoselective ligation. Using the described tandem combinatorial biosynthesis/chemoselective ligation approach we will generate libraries of compounds, as well as generate vancomycin/membrane-active antibiotic chimerae. The proposed research will potentially produce new drug leads and elucidate structure activity relationships.