The Chemoglycorandomization of Natural Products

描述(申请人提供)：碳水化合物修饰的万古霉素类似物是克服细菌对这种最后一道防线抗生素耐药性的非常有希望的线索。不幸的是，几乎没有方法可以改变天然产物的碳水化合物配体。这一限制使得结构-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来创建新的碳水化合物衍生的天然产物类似物，并通过化学选择性连接进一步使这些产物多样化。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。这项拟议的研究可能会产生新的药物先导，并阐明结构活性关系。

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.