Studies Toward Hybrid Glycopeptide Antibiotics

描述(申请人提供)：抗生素耐药性已经成为医院和社区的一个主要问题，我们需要新的抗生素来预防公共卫生危机。这项研究旨在了解一些糖肽衍生物克服抗生素耐药性的分子基础，并了解莫诺霉素的作用机制。莫诺霉素是一种有效的抗生素，可抑制主要但未被开发的抗菌靶点--转糖苷酶。建议了合成糖脂衍生物和莫诺霉素类似物的有效的化学酶和合成路线，所制备的化合物将在细胞和酶分析中进行测试，以提供对结构-活性关系的洞察。我们还建议进行实验，以了解糖肽类似物如何克服VANA和VANB抗性的机制基础。更好地了解克服耐药性的机制，结合有关活性如何随结构变化的信息，可能导致开发新的抗生素，以克服常见形式的抗生素耐药性。

DESCRIPTION (provided by applicant): Antibiotic resistance has become a major problem in hospitals and in the community and we need new antibiotics to forestall a public health crisis. The research proposed here is directed towards understanding the molecular basis by which some glycopeptide derivatives overcome antibiotic resistance and towards understanding the mechanism of action of moenomycin, a potent antibiotic that inhibits a major but underexploited antibacterial target, the transglycosyalses. Efficient chemoenzymatic and synthetic routes to glycolipid derivatives and moenomycin analogues are proposed, and the compounds that are made will be tested in both cell-based and enzymological assays in order to provide insight into structure-activity relationships. We also propose experiments to understand the mechanistic basis for how glycopeptide analogues overcome vanA and vanB resistance. A better understanding of the mechanisms by which resistance can be overcome, combined with information on how activity varies as a function of structure, could lead to the development of new antibiotics that overcome common forms of antibiotic resistance.