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

项目概要 多重耐药肺炎克雷伯菌感染是对人类健康和死亡率的主要威胁 利率正在稳步上升。肺炎克雷伯菌的定义特征之一是坚固的胶囊，有助于 抵抗人体补体系统、宿主抗菌肽和最后的治疗手段 多粘菌素。然而，尚未做出重大努力来确定活性肽的属性 绕过肺炎克雷伯菌的荚膜。我之前发现了肽的一种新机制 肺炎克雷伯菌的荚膜屏障被破坏。我假设氨基酸残基发生了变化 理化特性并允许穿透胶囊。在本次K99阶段 我的提案将：1）定义宿主防御肽如何适应胶囊破坏的新机制；和 2) 确定能够破坏肺炎克雷伯菌荚膜的更广泛的理化特征。 这些目标的目的是确定经过充分研究的宿主防御肽如何适应宿主防御机制 使用生化和生物物理实验破坏胶囊并确定理化属性 允许肽聚集并破坏肺炎克雷伯菌荚膜。 R00阶段将建立在 K99 相，鉴定与肽聚集的细菌荚膜的结构成分 揭示治疗胶囊去除对肺炎克雷伯菌感染过程的影响 在 K99 相中发现的肽。 K99/R00奖项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 过渡到独立研究职位。该奖项完成的研究结果将提供 更好地了解荚膜的肽破坏以及这如何改变克雷伯氏菌的感染过程。 肺炎杆菌。

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.