Refining our understanding of antimicrobial peptide mediated disruption of the Klebsiella pneumoniae capsule

项目摘要 多重耐药肺炎克雷伯菌细菌感染是人类健康的主要威胁，因为死亡率 利率正在稳步上升。肺炎克雷伯菌的主要特征之一是坚固的胶囊，可以帮助 抵抗人类补体系统、宿主抗菌肽和最后的治疗方法 多粘菌素。然而，还没有重大的努力来鉴定允许活性多肽的属性 绕过肺炎克雷伯菌的包膜。我之前发现了一种新的多肽机制 肺炎克雷伯菌的囊膜屏障破裂。我假设有氨基酸残基会改变 物理化学属性和允许穿透胶囊。在此的K99阶段 建议I将：1)定义宿主防御肽如何适应新的包膜破坏机制；以及2) 确定允许肺炎克雷伯菌胶囊破裂的更广泛的一组物理化学特征。 这些目标的目的是确定研究良好的宿主防御肽在多大程度上适合 利用生化和生物物理实验测定胶囊破碎度和确定其理化性质 允许肺炎克雷伯菌胶囊的多肽聚集和崩解。R00阶段将建立在 K99相，用于鉴定与多肽聚集的细菌胶囊的结构成分 揭示治疗性包膜取出对肺炎克雷伯菌感染过程的影响 K99相中发现的多肽。K99/R00奖将使我能够利用广泛的资源 在德克萨斯大学奥斯汀分校与我的导师团队合作以确保成功 过渡到独立的研究岗位。该奖项中完成的研究结果将提供一个 更好地理解了多肽对衣壳的破坏以及这如何改变了K。 肺炎。

Project Summary Multi-drug resistant Klebsiella pneumoniae bacterial infections are a major threat to human health as mortality rates are steadily on the rise. One of the defining characteristics of K. pneumoniae is a robust capsule that aids in resistance to the human complement system, host antimicrobial peptides, and last resort therapeutic polymyxins. However, there have not been significant efforts to identify the attributes that allow active peptides to bypass the capsule of K. pneumoniae. I have previously discovered a novel mechanism of peptide disruption of the capsule barrier of K. pneumoniae. I hypothesize there are amino acid residues that change the physiochemical attributes and allow for penetration through the capsule. During the K99 phase of this proposal I will: 1) Define how host defense peptides fit into the novel mechanism of capsule disruption; and 2) Identify broader set of physiochemical characteristics that allow for disruption of the K. pneumoniae capsule. The objective of these aims is to determine how well studied host defense peptides fit into the mechanism of capsule disruption using biochemical and biophysical experiments and determine the physiochemical attributes that allow for peptide aggregation and disruption of K. pneumoniae capsule. The R00 phase will build on the K99 phase, to identify the structural components of bacterial capsule that is aggregating with peptides and reveal the implications of therapeutic capsule removal on the infection process of K. pneumoniae using peptides discovered in the K99 phase. The K99/R00 award will allow me to utilize the extensive resources available at the University of Texas at Austin while working with my mentor team to ensure successful transition to an independent research position. The results of the studies completed in this award will provide a greater understanding of peptide disruption of capsule and how this changes the infection process of K. pneumoniae.