STAPHYLOCIDAL MECHANISM OF PLATELET MICROBICIDAL PROTEIN

血小板杀菌蛋白的杀菌机制

• 批准号: 6124395
• 负责人: ARNOLD S BAYER
• 金额: $ 19.86万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124395
• 关键词: Staphylococcus aureus; antibacterial agents; bactericidal immunity; chemical binding; genetic strain; host organism interaction; laboratory rabbit; membrane biogenesis; platelet factor 4; platelets; thrombin

Traditionally, platelets have been thought to promote the development of endovascular infections such as infective endocarditis (lE), by providing a adhesive surface upon damaged endothelium for colonization by circulating microorganisms. In contrast, recent evidence suggests that platelets serve an important host defense role against the development of endovascular infections at sites of endothelial damage via local secretion of endogenous microbicidal peptides , termed thrombin-induced platelet microbicidal protein or tPMP. Preliminary studies revealed the following data: i) tPMP kills the most common endovascular pathogens in nM concentrations; ii) microbial strains from bacteremic patients without IE were significantly more susceptible in vitro to the microbicidal action of tPMP than strains from bacteremic patients with IE. This suggested that phenotypic tPMP- resistance provides the organism with a survival advantage as regards induction of IE; iii) tPMP is synergistic in combination with conventional antibiotics in the killing and growth.inhibition of S. aureus ; and iv) the bacterial cell membrane appears to be a primary target for tPMP-induced lethality.The overall purpose of the current proposal is to define the fundamental microbicidal mechanisms of tPMP against S. aureus, the most virulent and commonest overall cause of endovascular infections, by: i) quantifying tPMP binding to the staphylococcal membrane; ii) delineating the role of bacterial transmembrane potential in the staphylocidal actions tPMP; iii) identifying membrane assembly of tPMP and subsequent membrane permeabilization and pore formation by tPMP; and iv) defining the mechanisms of phenotypic tPMP resistance, using genetically-related staphylococcal strains from a common genomic background which differ phenotypically in tPMP susceptibility. These studies may eventually define novel staphylocidal targets or unique staphylocidal mechanisms. These studies will also provide a solid foundation for defining the staphylocidal domains of tPMP by molecular biologic techniques. tPMP will also serve as a design template for development of synthetic congeners with potent antimicrobial activity.

传统上，血小板被认为可以促进 血管内感染，例如感染性心内膜炎（lE），通过提供 受损内皮上的粘附表面，通过循环进行定植 微生物。相反，最近的证据表明血小板可以发挥作用 对血管内病变发展具有重要的宿主防御作用 通过局部分泌内源性内皮损伤部位的感染 杀微生物肽，称为凝血酶诱导血小板杀微生物 蛋白质或 tPMP。初步研究揭示了以下数据： i) tPMP 以 nM 浓度杀死最常见的血管内病原体；二） 无 IE 菌血症患者的微生物菌株显着 在体外比菌株更容易受到 tPMP 的杀菌作用 来自 IE 菌血症患者。这表明表型 tPMP- 抵抗力为生物体提供了以下方面的生存优势 IE的诱导； iii) tPMP 与传统的组合具有协同作用 抗生素对金黄色葡萄球菌的杀灭和生长抑制作用；和 iv) 细菌细胞膜似乎是 tPMP 诱导的主要靶标 当前提案的总体目的是定义 tPMP 对金黄色葡萄球菌的基本杀菌机制 血管内感染的致命且最常见的总体原因，由：i) 量化 tPMP 与葡萄球菌膜的结合； ii) 描绘 细菌跨膜电位在杀葡萄球菌作用中的作用 tPMP； iii) 识别 tPMP 的膜组件和后续的 tPMP 的膜透化和孔形成；和 iv) 定义 表型 tPMP 抗性的机制，利用遗传相关 来自共同基因组背景但不同的葡萄球菌菌株 tPMP 易感性的表型。这些研究可能最终定义 新颖的杀葡萄球菌靶点或独特的杀葡萄球菌机制。这些 研究还将为定义杀葡萄球菌提供坚实的基础 通过分子生物学技术确定 tPMP 的结构域。 tPMP也将服务 作为开发具有强效的合成同系物的设计模板 抗菌活性。