MOLECULAR AND STRUCTURAL BASES OF POLYMYXIN RESISTANCE

描述（改编自申请人摘要）： 对多种病原体表现出抗性的细菌病原体的分离 抗生素产生了对新治疗剂的迫切需求。 自然 宿主防御肽和来自抗菌蛋白的肽片段 吞噬宿主细胞目前正被开发为抗微生物剂。 鼠伤寒沙门氏菌的pmrA基因座编码一个双组分调节蛋白， 系统-PmrA/PmrB-控制对多粘菌素B和抗菌剂的抗性 人嗜中性粒细胞的肽/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 阴离子，导致多粘菌素B和阳离子的结合减少 PMNs的肽/蛋白质。 提出实验来表征 分子细节PmrA激活的基因是多粘菌素所需的 B-抗性，并检查LPS缺陷突变体中LPS的结构。 PmrA调控基因。 pH值和二价阳离子 浓度调节电阻将通过分析 PhoP/PhoQ和PmrA/PmrB双组分之间的相互作用 监管制度。 这些研究的结果应该提供一个 沙门氏菌抵抗阳离子的能力的详细分子图像 抗菌肽 此外，它还可能导致新的战略， 阻止介导抗菌药物耐药性的决定簇的表达 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.