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Prevention of infectious diseases through inhibition of bacterial adherence to host tissues.

通过抑制细菌粘附到宿主组织来预防传染病。

基本信息

批准号：
16390540
负责人：
ITO Hiro-O
金额：
$ 8.13万
依托单位：
The University of Tokushima (2005)Kagoshima University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Infective endocarditis is often caused by passage of oral endogenous bacteria into the blood stream. Such bacteremia occurs after tooth extraction, and occasionally even after brushing of the teeth. Abnormal or damaged heart valves, including artificial valves, show high risk of infection. Antibiotics are widely used to prevent this infection, however, frequent use of these have resulted in the generation of resistant mutants, which generate serious social problems. Thus, the development of more effective and safer drugs for the prevention of such infections is very desirable. The adhesion of bacteria to fibronectin, one of the major extracellular matrix protein exposed on the wound endocardia, is considered critical for the infection. We have previously found a novel mode of interaction between endocarditis-causing bacteria and human fibronectin. The present study focuses on the discovery of candidate compounds that inhibit the association between microorganisms and fibronectin. Positional scanning libraries (PSL) with N-terminal biotinylated 6-mer peptides have been constructed and screened for binding to a monoclonal antibody for fibronectin that inhibits the bacterial fibronectin-binding. The consensus sequences derived from these experiments are expected to be structural mimetics of the local structure of fibronectin involved in the bacterial adhesion. Since individual synthetic 6-mer peptides did not show the desired action, discontinuous epitopes can be envisaged and therefore a 9-mer-PSL was constructed to reveal conformational epitopes. In the second Library, several 9-mer peptides based on the screening were synthesized and gave improved results.

感染性心内膜炎通常是由口腔内源性细菌进入血流引起的。这种菌血症发生在拔牙后，偶尔甚至在刷牙后。异常或受损的心脏瓣膜，包括人工瓣膜，显示感染的高风险。抗生素被广泛用于预防这种感染，然而，频繁使用这些抗生素导致产生耐药突变体，这产生了严重的社会问题。因此，非常需要开发用于预防此类感染的更有效和更安全的药物。纤维连接蛋白是心内膜伤口处暴露的主要细胞外基质蛋白之一，细菌与纤维连接蛋白的粘附被认为是感染的关键。我们以前发现了一种新的模式之间的相互作用的心内膜炎引起的细菌和人纤连蛋白。本研究的重点是发现候选化合物，抑制微生物和纤连蛋白之间的关联。已经构建了具有N-末端生物素化的6-mer肽的位置扫描文库（PSL），并筛选了其与抑制细菌纤连蛋白结合的纤连蛋白的单克隆抗体的结合。从这些实验中获得的共有序列预期是参与细菌粘附的纤连蛋白的局部结构的结构模拟物。由于单独的合成6-mer肽没有显示出所需的作用，可以设想不连续的表位，因此构建了9-mer-PSL以揭示构象表位。在第二个文库中，在筛选的基础上合成了几个9-mer肽，并给出了改进的结果。