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

加深我们对抗菌肽介导的肺炎克雷伯菌荚膜破坏的理解

• 批准号: 10762694
• 负责人: Renee Fleeman
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762694
• 关键词: Adjuvant; Amino Acids; Anti-Bacterial Agents; Antibiotic Resistance; Award; Bacterial Antibiotic Resistance; Bacterial Capsules; Bacterial Infections; Binding; Biochemical; Biophysics; Bypass; Characteristics; Chemicals; Communicable Diseases; Data; Ensure; Excision; Goals; Health; Host Defense; Human; Immune system; Infection; Innate Immune System; Klebsiella pneumoniae; Knowledge; Libraries; Mass Spectrum Analysis; Mediating; Membrane; Mentors; Multi-Drug Resistance; Nature; Penetration; Peptides; Phagocytosis; Phase; Polymyxins; Positioning Attribute; Process; Public Health; Research; Research Personnel; Resistance; Resources; Role; Structure; Testing; Texas; Therapeutic; Transmission Electron Microscopy; Universities; Variant; Virulence; Work; alpha helix; antimicrobial; antimicrobial peptide; austin; beta pleated sheet; capsule; complement system; design; experimental study; immune clearance; mortality; mutant; novel; novel strategies; peptide structure; prevent; resistant Klebsiella pneumoniae; scaffold; therapeutic development

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.

项目摘要 多重耐药肺炎克雷伯菌感染是人类健康的主要威胁， 利率稳步上升。K.肺炎是一个强大的胶囊， 对人补体系统、宿主抗微生物肽和最后的治疗手段具有抗性 多粘菌素。然而，还没有显著的努力来鉴定允许活性肽的属性， 绕过K的胶囊肺炎。我之前发现了一种新的肽机制 破坏K.肺炎。我假设有些氨基酸残基 物理化学属性并允许穿透胶囊。在K99阶段， 建议我将：1）定义宿主防御肽如何适应胶囊破裂的新机制; 2） 确定更广泛的理化特性，允许破坏K。肺炎荚膜 这些目标的目的是确定如何充分研究宿主防御肽适合的机制， 使用生物化学和生物物理实验破坏胶囊，并确定理化属性 允许肽聚集和K的破坏。肺炎荚膜R 00阶段将建立在 K99阶段，鉴定与肽聚集的细菌被膜的结构成分， 揭示了治疗胶囊去除对K.肺炎使用 在K99阶段发现的肽。K99/R 00奖将使我能够利用广泛的资源， 我在德克萨斯大学奥斯汀分校与我的导师团队合作， 向独立研究方向转型。在这个奖项中完成的研究结果将提供一个 进一步了解肽破坏荚膜以及这如何改变K. 肺炎。