Synthesis and Testing of Neoglycoside Glycopeptide Prototypes

描述（由申请人提供）：本I期提案旨在开发针对VanA耐药和VanB耐药微生物的糖肽新糖苷类。这些化合物的临床相关性源于VRE（万古霉素耐药肠球菌，以及最近的葡萄球菌）感染的急剧上升，仅在美国，VRE感染从1989年的低于0.5%上升到2000年的>30%。耐万古霉素微生物的增加正在造成严重的公共卫生问题，使治疗感染变得极其困难，并增加了患者在医院感染的风险。需要开发新的化合物来克服这个问题。万古霉素分子中连接的碳水化合物的修饰已被证明是克服微生物耐药机制的关键。然而，可用的碳水化合物修饰的万古霉素类似物的数量受到母体糖肽天然产物的合成复杂性的限制。新糖随机化是一种用于1步糖连接的稳健化学方法，其不需要任何先前的糖保护或活化。该方法有望在发现新的基于万古霉素的治疗剂方面提供明显的优势。在这项工作中，我们将合成2种类型的新糖苷类糖肽原型分子，1种靶向VanA抗性，另一种靶向VanB抗性。这些分子将接受有效性筛选。随着万古霉素耐药细菌感染发病率的急剧增加，迫切需要新的抗菌治疗剂。我们的工作使用一种独特的技术，通过将糖连接到天然产物的核心分子上来创造万古霉素的新型衍生物，并将专门设计用于克服耐药菌株。

DESCRIPTION (provided by applicant): This Phase I proposal is to develop glycopeptide neoglycosides against VanA-resistant and VanB-resistant organisms. The clinical relevance of such compounds stems from the sharp rise in VRE (vancomycin-resistant enterococci, and more recently staphylococci) infections from below 0.5% in 1989 to >30% in 2000 in the U.S. alone. This rise in vancomycin-resistant organisms is causing a serious public health problem, making it extremely difficult to treat infections, and also increasing the risk of patients acquiring infections while in a hospital. New compounds need to be developed in order to overcome this problem. Modification of the attached carbohydrates in the vancomycin molecule has proven to be key to overcoming the mechanisms of resistance in microbes. Yet, the number of available carbohydrate-modified vancomycin analogs is limited by the synthetic complexity of the parent glycopeptide natural product. Neoglycorandomization is a robust chemical method for 1 step sugar ligation which does not require any prior sugar protection or activation. This method is anticipated to provide a clear advantage in the discovery of new vancomycin-based therapeutics. In this work, we will synthesize 2 types of neoglycoside glycopeptide prototype molecules, 1 targeting VanA resistance, and the other, VanB resistance. These molecules will be subjected to screening for effectiveness. With the dramatic increase in the incidence of vancomycin-resistant bacterial infections, there is a critical need for new antibacterial therapeutics. Our work uses a unique technology to create novel derivatives of vancomycin by attaching sugars to the core molecule of the natural product, and will be specially designed to overcome resistant strains.