CATALYTIC ANTIBIOTICS

万古霉素和杆菌肽是肽类天然产物 其通过抑制肽聚糖而发挥抗菌活性 生物合成 万古霉素和杆菌肽有一个共同的特性 --它们的靶点不是蛋白质和核酸等大分子， 酸，而是肽聚糖生物合成中的中间体。 万古霉素和杆菌肽结合到它们的靶点（C-末端）。 在万古霉素的情况下，肽聚糖前体的一部分，和 在杆菌肽的情况下为焦磷酸杆菌异戊二烯酯）， 有效地将它们与细胞壁生物合成机制隔离。 我们已经开展了一项研究计划， 半合成修饰这些试剂，考虑到三个目标：1） 增强与细胞靶点的结合，2）赋予它们特异性 靶向活性，和3）赋予它们催化活性。 我们认为，这样的修饰可以提高效力和/或 这些抗生素的功效。 到目前为止，我们已经开发出 半合成万古霉素甲酰胺的一般方法，和 进行杆菌肽的全合成。 我们已经发现 万古霉素和相关药物的氨基甲酸酯水解酶活性 糖肽抗菌剂，并开发了新的方法， 探测糖肽：肽复合物内的微环境。 一些 我们的万古霉素甲酰胺衍生物表现出增强的 相对于万古霉素的抗菌效力，包括有前途的 抗万古霉素耐药肠球菌的活性。 在这些和我们的 计划未来的研究，FAB-MS和相关技术是至关重要的， 合成结构的适当结构表征。

Vancomycin and bacitracin are peptide-derived natural products which exert antibacterial activity via inhibition of peptidoglycan biosynthesis. Vancomycin and bacitracin share an interesting property -- their targets are not macromolecules such as proteins and nucleic acids, but rather intermediates in peptidoglycan biosynthesis. Vancomycin and bacitracin bind to their targets (the C-terminal portion of peptidoglycan precursors in the case of vancomycin, and bactoprenyl pyrophosphate in the case of bacitracin), which effectively sequesters them from the cellwall biosynthesis machinery. We have undertaken a research program to synthesize and/or semisynthetically modify these agents, with three goals in mind: 1) to enhance binding to cellular targets, 2) to endow them with specific targetting activities, and 3) to endow them with catalytic activity. We believe that such modifications may enhance the potency and/or range of efficacy of these antibiotics. To date, we have developed general methods for the semisynthesis of vancomycin carboxamides, and undertaken the total synthesis of bacitracins. We have discovered unprecedented carbamate hydrolase activity by vancomycin and related glycopeptide antibacterial agents, and developed novel methods for probing microenvironments within glycopeptide:peptide complexes. Some of our vancomycin carboxamide derivatives exhibit enhanced antibacterial potency relative to vancomycin, including promising activity against vancomycin-resistant enterococci. In these and our planned future studies, FAB-MS and related techniques are critical to proper structural characterization of synthetic structures.