Specific Inhibition of Chlamydia with Hydroxamates

描述（由申请人提供）：这项新的R21资助将探索衣原体感染的新机制。衣原体是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、不孕症、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。衣原体感染也使人容易感染艾滋病毒。衣原体是专性细胞内细菌，通过在被感染宿主细胞内复制和破坏细胞以及引起炎症反应而引起病理变化。该项目的长期目标是通过定义成功感染衣原体所必需的新细菌成分来阐明衣原体疾病的发病机制，并通过这些新成分探索预防和治疗衣原体疾病的新策略。据观察，衣原体的细胞内发育对金属蛋白酶抑制剂家族（即羟基酸盐）高度敏感。这些抑制剂似乎对衣原体有特异性，因为它们不影响大肠杆菌和其他常见细菌的生长。羟肟酸处理逆转了衣原体感染引起的细胞增殖抑制。一种指定为GR10的沙眼衣原体突变体对羟酸盐治疗具有高度抗性。这些发现表明，一种对羟酸盐敏感的衣原体蛋白——很可能是锌金属蛋白酶——是衣原体感染所必需的，并且可能作为衣原体感染干预的理想靶点。本研究将确定对衣原体生长具有高效抑制作用的羟肟化合物的分子靶点。本项目还将研究金属蛋白酶是否在衣原体发病机制中发挥作用，并进一步探索羟肟类化合物在衣原体感染治疗中的应用。

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.