CATALYTIC ANTIBIOTICS

万古霉素和杆菌肽是多肽衍生的天然产物。 它们通过抑制肽聚糖发挥抗菌活性 生物合成。万古霉素和杆菌肽有一个有趣的特性 --他们的目标不是蛋白质和核等大分子 酸，而不是肽聚糖生物合成的中间体。 万古霉素和杆菌素与其靶标结合(C-末端 在万古霉素的情况下，部分肽聚糖前体，以及 在杆菌肽的情况下)，其 有效地将它们从细胞壁生物合成机器中隔离出来。 我们已经开展了一项研究计划，以合成和/或 半合成地修饰这些代理，心中有三个目标：1) 为了增强与细胞靶点的结合，2)赋予它们特定的 靶向活性；3)赋予它们催化活性。 我们认为，这种修改可以增强效力和/或 这些抗生素的药效范围。到目前为止，我们已经开发出 万古霉素羧胺类化合物半合成的一般方法 承担了杆菌菌素的全合成。我们发现 万古霉素及其相关物质对氨基甲酸酯水解酶活性的影响 糖肽抗菌剂，并开发了新的方法来治疗 探索糖肽中的微环境：多肽复合体。一些人 我们的万古霉素甲酰胺衍生物显示出增强的 相对于万古霉素的抗菌力，包括前景看好 抗万古霉素耐药肠球菌的活性。在这些和我们的 有计划的未来研究、FAB-MS和相关技术对于 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.