GLYCOPEPTIDE ANTIBOTIC MECHANISM AND RESISTANCE

这项研究的目标是开发新药， 治疗耐药的革兰氏阳性细菌感染。 为 在过去的40年里，万古霉素一直是最后的抗生素， 革兰氏阳性菌 通过交换遗传信息， 病原菌，最显著的是肠球菌菌株， 葡萄球菌，已发展耐万古霉素和其他成员 糖肽类抗生素家族，包括伊瑞霉素和 替考拉宁。这些糖肽类抗生素抑制细菌细胞壁 通过干扰转糖苷作用进行生物合成， 肽聚糖的转肽作用。 一种形式的抵抗导致 来自肽聚糖中D-丙氨酸取代D-乳酸。 也观察到其他形式的抵抗，但效果不太好 表征了 万古霉素和伊瑞霉素似乎起到头对- 尾型二聚体，通过其肽的氢键结合 骨干 这项研究的重点是糖的作用， 关键但遥远的万古霉素和伊瑞霉素组分 从肽聚糖结合位点。 这项研究将确定如何 糖促进体内共价二聚体的形成， 保留其肽骨架的氢键，以及 万古霉素和伊瑞霉素中糖立体化学的差异影响 共价二聚 共价二聚体，实际上是药物 代谢物，将被合成并针对万古霉素- 敏感和耐万古霉素的革兰氏阳性菌。 共价 二聚体也将研究相互作用和反应 敏感和耐药的细菌细胞壁靶标 细菌 这项研究将进一步了解如何 微生物的次级代谢产物被设计为 抗生素，而不是太有毒的微生物， 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.