Specific Inhibition of Chlamydia with Hydroxamates

描述(由申请人提供)：这项新的R21拨款将探索一种治疗衣原体感染的新机制。衣原体是一种广泛存在的人类病原体，可导致多种疾病，包括可预防的失明、盆腔炎、不孕不育、肺炎和关节炎。在美国，生殖器衣原体感染是所有性传播感染中最普遍的。衣原体感染也使个人容易感染艾滋病毒。衣原体是专性细胞内细菌，通过在受感染宿主的细胞内复制和破坏细胞，并通过引发炎症反应而引起病理变化。该项目的长期目标是通过确定衣原体感染成功所必需的新的细菌成分来阐明衣原体疾病的发病机制，并通过靶向这些新成分来探索预防和治疗衣原体疾病的新策略。已经观察到衣原体的细胞内发育对被称为异羟甲酸酯的金属蛋白酶抑制剂家族高度敏感。这些抑制剂似乎对衣原体具有特异性，因为它们不影响大肠杆菌和其他常见细菌的生长。羟基磷灰石可逆转衣原体感染对细胞增殖的抑制作用。沙眼衣原体突变株GR10已被分离到，该突变株对异羟甲酸酯具有高度抗性。这些发现表明，衣原体感染需要一种对异羟甲酸酯敏感的衣原体蛋白--很可能是一种锌金属蛋白酶，并可能成为干预衣原体感染的理想靶点。这项研究将确定高效抑制衣原体生长的羟基氧化物化合物的分子靶点。该项目还将探讨金属蛋白酶是否在衣原体发病中发挥作用，并将进一步探索羟基氧化物用于治疗衣原体感染的用途。

DESCRIPTION (provided by applicant): This new R21 grant will explore a novel mechanism for chlamydial infection. Chlamydiae are widespread human pathogens responsible for a variety of diseases including preventable blindness, pelvic inflammatory disease, infertility, pneumonia and arthritis. In the United States, genital chlamydial infection is the most prevalent of all sexually transmitted infections. Chlamydial infection also predisposes individuals to HIV infection. Chlamydiae are obligate intracellular bacteria, and cause pathological changes by replicating within and disrupting the cells of infected hosts, and by eliciting inflammatory reactions. The long-term goal of this project is to elucidate the pathogenesis of chlamydial disease by defining novel bacterial components essential for successful chlamydial infection and to explore a new strategy for prevention and treatment of chlamydial disease by targeting these novel components. It has been observed that the intracellular development of Chlamydiae is highly sensitive to the family of metalloprotease inhibitors referred to as hydroxamates. These inhibitors appear to have specificity for Chlamydiae since they do not affect growth of Escherichia coli and other common bacteria species. Hydroxamate treatment reversed the inhibition of cell proliferation caused by chlamydial infection. A Chlamydia trachomatis mutant designated GR10 that is highly resistant to hydroxamate treatment has been isolated. These findings suggest that a chlamydial protein that is sensitive to hydroxamates - most likely a zinc metalloprotease - is required for chlamydial infection, and may serve as an ideal target for the intervention of chlamydial infection. This research will identify the molecular target of the hydroxamic compound that is highly effective in inhibiting chlamydial growth. This project will also address whether the metalloprotease plays a role in chlamydial pathogenesis, and will further explore the utility of hydroxamic compounds for treating chlamydial infection.