GLYCOPEPTIDE ANTIBOTIC MECHANISM AND RESISTANCE

糖肽抗体机制及耐药性

• 批准号: 2727013
• 负责人: TAD H KOCH
• 金额: $ 7.13万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2727013
• 关键词: Enterococcus; Staphylococcus aureus; X ray crystallography; antibiotics; carbohydrate structure; chemical conjugate; doxorubicin; drug design /synthesis /production; drug metabolism; drug resistance; formaldehyde; glycopeptides; gram positive bacteria; high performance liquid chromatography; mass spectrometry; stereochemistry; vancomycin

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.

拟议研究的目的是开发新药 抗性，革兰氏阳性细菌感染的治疗。 为了 过去40年，万古霉素一直是Last Resort的抗生素 革兰氏阳性细菌。 通过交换遗传信息， 致病细菌，最著名的是肠球菌菌株和 葡萄球菌已经对万古霉素和其他成员产生了抗药性 这个糖肽抗生素的家族，包括尿霉素和 teicoplanin。这些糖肽抗生素抑制细菌细胞壁 通过干扰糖化和 肽聚糖的转换。 阻力结果一种形式 从肽聚糖中D-丙氨酸代替D-丙氨酸。 已经观察到其他形式的抗性，但不太好 特征。 万古霉素和脑霉素似乎是从头到尾的作用 尾型二聚体，通过其肽的氢键相关 骨干。 拟议的研究重点是糖的作用 万古霉素和脑霉素的成分至关重要但很遥远 来自肽聚糖结合位点。 研究将确定如何 糖促进了共价二聚体的体内形成 保留其肽骨架的氢键，以及如何 万古霉素和脑膜霉素中的糖立体化学差异会影响 共价二聚化。 共价二聚体，实际上是药物 代谢物将与两个万古霉素合成和评估 敏感和万古霉素抗革兰氏阳性细菌。 共价 还将研究二聚体有关的相互作用和反应 具有敏感和抗性的细菌细胞壁目标 细菌。 这项研究将进一步了解如何 微生物的次生代谢物被设计为起作用 抗生素没有对产生的微生物过多毒性 他们。