Chemoenzymatic Synthesis of New Glycopeptide Antibiotics

描述(由申请人提供)： 对糖肽残基4和6上的碳水化合物部分进行化学酶修饰，在产生针对威胁生命的万古霉素耐药病原体的新疗法方面具有巨大的潜力。然而，关于七肽6位残基上各种糖的结合作用的研究还没有被探索过。为了促进各种糖在这个位置的附加，将表达和纯化替考拉宁酶tGtfA。我们将研究它的底物选择性，以便将其作为一种潜在的催化剂来将各种碳水化合物转移到七肽支架上。此外，基于参与糖肽生物合成的糖基转移酶的已知结构，将设计出具有新活性的嵌合糖基转移酶。此外，还将对两个三糖基化糖肽进行还原烷基化反应，不仅是为了发现新的抗生素，也是为了提高化学酶法合成糖肽变体的效率。

DESCRIPTION (provided by applicant): Chemoenzymatic modifications of the carbohydrate moieties on residue 4 and 6 of glycopeptide have great potential in generating new therapeutics against life-threatening vancomycin-resistant pathogens. However, the studies on the attachment of a variety of sugars at residue 6 of the heptapeptide have not been explored. To facilitate the appendage of various sugars at this position, a teicoplanin enzyme tGtfA will be expressed and purified. Its substrate preference will be studied so that it may be used as a potential catalyst to transfer various carbohydrates to the heptapeptide scaffolds. Moreover, chimeric glycosyltransferase with novel activities will be engineered based on the known structures of glycosyltransferases involved in glycopeptide biosynthesis. In addition, reductive alkylation of two triglycosylated glycopeptides will be carried out not only for discovering new antibiotics but also for improving the efficiency of the chemoenzymatic synthesis of glycopeptide variants.