PEPTIDES ACTIVE AGAINST INTRACELLULAR PATHOGENIC DISEASE

描述：细胞内细菌引起广泛的 人类的慢性致命性疾病，包括肺结核和波浪性疾病 发热(布鲁氏菌病)，由结核分枝杆菌和 布鲁氏菌分别为流产布鲁氏菌。这些细菌对人来说很难 免疫系统会杀死并需要肺部抗生素治疗，因为它们 隐藏对宿主巨噬细胞的洞察。对于这些感染中的许多，甚至 在疾病症状消除后，残留的活细菌 通常留在被称为肉芽肿的巨噬细胞团块中。这 残留感染通常是无害的，但会导致复发。 感染，这通常会导致包括免疫成分的死亡 像艾滋病患者这样的个人。拟议研究的目的是 探索治疗细胞内致病的新机制 通过螺旋两亲性选择性裂解感染的巨噬细胞 多肽。这项工作中的新多肽含有很大比例的 非自然的阿尔法，阿尔法分布的氨基酸，这使得它们高度 即使它们相对较短(10个氨基酸)也是螺旋的。主 假说是这些多肽选择性地破坏感染的巨噬细胞 与细胞内的病原体一起，将病原体从其 保护性利基，从而使它们更容易受到添加的抗生素的影响 和免疫反应。这一新的间接的机制和范围 抗菌活性及多肽结构要求 对观察到的选择性负责的人将根据 具体目的如下：(1)探讨多肽诱导的机制 易感巨噬细胞的体外裂解。显微镜实验使用 标记的细菌和多肽将确定最佳浓度 感染巨噬细胞的选择性裂解及其浓度 结合并裂解巨噬细胞。(2)确定最活跃的 以及体外和体内选择性多肽或多肽模拟物 活动。从目前已知的最活跃的多肽开始 多肽的结构和大小会有所不同，以确定所需的 用于裂解感染的巨噬细胞的最佳活性和选择性。 (3)多肽剂量的优化及可能的协同作用 抗生素多肽对流产布鲁氏菌和布氏杆菌的影响 结核分枝杆菌体外和体内实验。多肽剂量 在添加和不添加抗生素的情况下，将使用感染的 肉芽肿和活体使用已建立的小鼠模型系统。

DESCRIPTION: Intracellular bacteria are responsible for a wide range of chronic and lethal disease in man including tuberculosis and undulant fever (brucellosis), which are caused by Mycobacterium tuberculosis and Brucella abortus, respectively. These bacteria are difficult for the immune system to kill and require lung antibiotic treatment because they hide insight the host's macrophages. For many of these infections, even after disease symptoms have been eliminated, residual live bacteria are often left in macrophage conglomerations known as granulomas. This residual infection is normally harmless, but is responsible for recurrence of infection, which often results in death for immuno-comprised individuals such as those with AIDS. The purpose of the proposed study is to explore a new mechanism for treating intracellular pathogenic diseases by selective lysis of infected macrophages by helical amphipathic peptides. The novel peptides in this work contain large percentages of unnatural alpha, alpha-distributed amino acids, which makes them highly helical even when they are relatively short (10 amino acids). The main hypothesis is that these peptides selectively destroy macrophages infected with intracellular pathogens, releasing the pathogens from their protective niche, thus making them more vulnerable to added antibiotics and the immune response. The mechanism and scope of this novel indirect antimicrobial activity as well as the peptide structural requirements responsible for the observed selectivity will be examined according the following Specific Aims: (1) To probe the mechanism of peptide induced lysis of susceptible macrophage in vitro. Microscopy experiments using labeled bacteria and peptides will determine optimal concentration for selective lysis of infected macrophages and at what concentration peptides bind to and lyse the macrophages. (2) Identification of the most active and selective peptide or peptide mimetic for in vitro and in vivo activity. Starting with the most active peptides currently known the peptide structure and size will be varied to determine what is required for optimal activity and selectivity in lysing of infected macrophages. (3) Optimization of multiple peptide doses and possible synergistic effects of peptides with antibiotics against Brucella abortus and Mycobacterium tuberculosis ex vivo and in vivo. Multiple peptides doses with and without added antibiotics will be studied ex vivo using infected granulomas and in vivo using established mouse model systems.