MOLECULAR AND STRUCTURAL BASES OF POLYMYXIN RESISTANCE

描述(改编自申请者摘要)：持续增长 多重抗性细菌病原菌的分离 抗生素产生了对新的治疗剂的迫切需求。天然 沙门氏菌抗菌蛋白中的抗菌肽和抗菌肽片段 吞噬宿主细胞目前正被开发为抗菌剂。 鼠伤寒沙门氏菌的pmrA基因编码一个双组分的调节性基因 PmrA/PmrB系统--控制对多粘菌素B和抗菌药物的耐药性 人中性粒细胞的多肽/蛋白质。多粘菌素B抗性突变株有 脂多糖中的化学修饰使其减少 阴离子，导致多粘菌素B与阳离子结合减少 中性粒细胞的多肽/蛋白质。建议进行实验，以表征 多粘菌素所需的PmrA激活基因的分子细节 B-抗性，并检测缺陷突变株的内毒素结构 PmrA调控的基因。PH和二价阳离子的作用机理 浓度调节电阻将通过分析 Phop/PhoQ与PmrA/PmrB双组分的相互作用 监管体系。这些研究的结果应该会提供一个 沙门氏菌抗阳离子能力的详细分子图谱 抗菌肽。此外，它还可能导致新的战略，以 阻止介导抗菌素耐药性的决定因素的表达 多肽，从而允许宿主清除细菌感染。

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.