GLYCOPEPTIDE ANTIBOTIC MECHANISM AND RESISTANCE

拟议研究的目标是开发用于治疗的新药 耐药革兰氏阳性细菌感染的治疗。对于 在过去的40年里，万古霉素一直是 革兰氏阳性细菌。通过交换遗传信息， 病原菌，最著名的肠球菌和 葡萄球菌对万古霉素和其他成员产生了抗药性 这一家族的糖肽抗生素，包括埃雷莫星和 替考拉宁。这些糖肽抗生素能抑制细菌细胞壁。 转糖苷化干扰生物合成 肽多聚糖的转肽。一种形式的抵抗导致 通过用D-丙氨酸取代肽聚糖中的D-乳酸。 也观察到了其他形式的耐药性，但效果不太好 特色化的。万古霉素和埃雷莫星似乎起到了头对头的作用 尾型二聚体，通过其多肽的氢键结合 脊椎骨。拟议的研究重点放在糖的作用上 万古霉素和埃雷莫星的关键成分 来自肽多聚糖结合部位。这项研究将确定 糖促进体内共价二聚体的形成，而 保持它们的多肽骨架的氢键，以及如何 万古霉素和埃雷霉素对糖立体化学的影响差异 共价二聚反应。共价二聚体，实际上是药物 代谢物，将被合成并与万古霉素- 对万古霉素敏感和耐药的革兰氏阳性细菌。共价 二聚体还将从相互作用和反应方面进行研究 在敏感和耐药的细菌细胞壁靶中 细菌。这项研究将提供对如何 微生物的次生代谢物被设计成 抗生素，而不是对产生 他们。

The goal of the proposed research is the development of new drugs for the treatment of resistant, gram-positive bacterial infections. For the past 40 years, vancomycin has been the antibiotic of last resort for gram-positive bacteria. Through exchange of genetic information, pathogenic bacteria, most notably strains of Enterococci and Staphylococci, have developed resistance to vancomycin and other members of this family of glycopeptide antibiotics, including eremomycin and teicoplanin. These glycopeptide antibiotics inhibit bacterial cell wall biosynthesis through interference of transglycosidation and transpeptidation of a peptidoglycan. One form of resistance results from a substitution of a D-alanine for a D-lactate in the peptidoglycan. Other forms of resistance have been observed but are less well characterized. Vancomycin and eremomycin appear to function as head-to- tail type dimers, associated through hydrogen bonding of their peptide backbones. The proposed research focuses on the role of the sugar components of vancomycin and eremomycin which are critical but remote from the peptidoglycan binding site. The research will establish how the sugars facilitate in vivo formation of covalent dimers while retaining the hydrogen bonding of their peptide backbones and how the difference in sugar stereochemistry in vancomycin and eremomycin affects covalent dimerization. Covalent dimers, which are actually drug metabolites, will be synthesized and evaluated against both vancomycin- sensitive and vancomycin-resistant gram-positive bacteria. Covalent dimers will also be studied with respect to interaction and reaction with bacterial cell wall targets in both sensitive and resistant bacteria. The research will provide a further understanding of how secondary metabolites of microorganisms are designed to function as antibiotics without being too toxic to the microorganism which creates them.