Specific Inhibition of Chlamydia with Hydroxamates

异羟肟酸盐对衣原体的特异性抑制

基本信息

批准号：
7027630
负责人：
HUIZHOU FAN
金额：
$ 18.98万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-15 至 2008-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7027630
关键词：
Chlamydiaceae antibacterial agents bacteria infection mechanism bacterial genetics bacterial proteins chlamydial disease drug screening /evaluation gene mutation hydroxamate laboratory mouse metalloendopeptidases microorganism culture nonhuman therapy evaluation pathologic process polymerase chain reaction reproductive system disorder chemotherapy reproductive system infection

项目摘要

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.

描述（由申请人提供）：这项新的R21赠款将探索一种新的衣原体感染机制。衣原体是负责各种疾病的广泛人类病原体，包括可预防的失明，盆腔炎症性疾病，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。衣原体感染也使个体患有艾滋病毒感染。衣原体是务实的细胞内细菌，并通过在内部复制和破坏感染宿主的细胞并引起炎症反应来引起病理变化。该项目的长期目标是通过定义成功的衣原体感染至关重要的新型细菌成分来阐明衣原体疾病的发病机理，并通过靶向这些新型成分来探索一种新的预防和治疗衣原体疾病的策略。已经观察到，衣原体的细胞内发育对被称为羟胺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。羟氨酸治疗逆转了衣原体感染引起的细胞增殖的抑制作用。已经分离出对羟氨酸治疗具有高度抗性的沙眼衣原体突变体。这些发现表明，对羟胺敏感的衣原体蛋白（最有可能是金属蛋白酶蛋白酶）是衣原体感染所必需的，并且可以作为干预衣原体感染的理想目标。这项研究将确定在抑制衣原体生长方面非常有效的羟胺化合物的分子靶标。该项目还将解决金属蛋白酶是否在衣原体发病机理中起作用，并将进一步探索羟型化合物对治疗衣原体感染的实用性。