MOLECULAR AND STRUCTURAL BASES OF POLYMYXIN RESISTANCE

多粘菌素抗性的分子和结构基础

• 批准号: 6497089
• 负责人: Eduardo Groisman
• 金额: $ 20.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497089
• 关键词: Salmonella typhimurium; antibacterial agents; antibiotics; bacterial genetics; carbohydrate structure; cations; drug resistance; gene expression; genetic mapping; genetic regulation; lipopolysaccharides; molecular cloning; mutant; peptides

DESCRIPTION (Adapted from applicant's abstract): The continuous increase in the isolation of bacterial pathogens exhibiting resistance to multiple antibiotics has created an urgent need for new therapeutic agents. Natural host-defense peptides and peptide fragments from antibacterial proteins of phagocytic host cells are currently being developed as antimicrobial agents. The pmrA locus of Salmonella typhimurium encodes a two-component regulatory system -PmrA/PmrB - that governs resistance to polymyxin B and antibacterial peptides/proteins of human neutrophils. Polymyxin B-resistant mutants have chemical modifications in the lipopolysaccharide (LPS) that make them less anionic, resulting in decreased binding of polymyxin B and cationic peptides/proteins of PMNs. Experiments are proposed to characterize in molecular detail the PmrA-activated genes which are required for polymyxin B-resistance and to examine the structure of the LPS in mutants defective in PmrA-regulated genes. The mechanism by which pH and divalent cation concentration modulate resistance will be examined by analyzing the interactions between the PhoP/PhoQ and the PmrA/PmrB two-component regulatory systems. The results from these studies should provide a detailed molecular picture for the capacity of Salmonella to resist cationic antibacterial peptides. Moreover, it may also lead to novel strategies to prevent expression of determinants that mediate resistance to antibacterial peptides, thereby allowing the host to clear bacterial infections.

描述（改编自申请人的摘要）： 分离具有多种抗性的细菌病原体 抗生素迫切需要新的治疗药物。 自然的 宿主防御肽和来自抗菌蛋白的肽片段 目前正在开发吞噬宿主细胞作为抗菌剂。 鼠伤寒沙门氏菌的 pmrA 基因座编码一个双组分调节因子 系统 -PmrA/PmrB - 控制对多粘菌素 B 和抗菌药物的耐药性 人类中性粒细胞的肽/蛋白质。 多粘菌素 B 抗性突变体 脂多糖 (LPS) 中的化学修饰使其更少 阴离子，导致多粘菌素 B 和阳离子的结合减少 PMN 的肽/蛋白质。 建议进行实验来表征 多粘菌素所需的 PmrA 激活基因的分子细节 B 抗性并检查 B 缺陷突变体中的 LPS 结构 PmrA 调节基因。 pH 值和二价阳离子的作用机制 将通过分析来检查浓度调节电阻 PhoP/PhoQ 和 PmrA/PmrB 双组分之间的相互作用 监管体系。 这些研究的结果应该提供一个 沙门氏菌抵抗阳离子能力的详细分子图片 抗菌肽。 此外，它还可能导致新的策略 防止介导抗菌素耐药性的决定簇的表达 肽，从而使宿主能够清除细菌感染。