Synthesis and Testing of Neoglycoside Glycopeptide Prototypes

描述（由申请人提供）：本I期提案旨在开发抗vana和vanb耐药生物的糖肽新糖苷。这些化合物的临床相关性源于仅在美国，VRE（万古霉素耐药肠球菌和最近的葡萄球菌）感染的急剧上升，从1989年的0.5%以下上升到2000年的30%以上。万古霉素耐药生物体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，也增加了病人在医院感染的风险。为了克服这个问题，需要开发新的化合物。万古霉素分子中附着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。新糖随机化是一种强大的一步糖结扎化学方法，不需要任何事先的糖保护或激活。该方法有望为发现新的万古霉素治疗方法提供明显的优势。在本研究中，我们将合成2种新糖苷类糖肽原型分子，一种针对VanA抗性，另一种针对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生率的急剧增加，迫切需要新的抗菌治疗方法。我们的工作使用了一种独特的技术，通过将糖附着在天然产物的核心分子上，创造出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.