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

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。这种菌血症在拔牙后发生，偶尔甚至在刷牙后也会发生。异常或受损的心脏瓣膜，包括人工瓣膜，显示出很高的感染风险。抗生素被广泛用于预防这种感染，但频繁使用抗生素导致了耐药突变株的产生，从而产生了严重的社会问题。因此，开发更有效和更安全的药物来预防这种感染是非常可取的。细菌对纤维连接蛋白的黏附被认为是感染的关键，纤维连接蛋白是伤口心内膜上暴露的主要细胞外基质蛋白之一。我们之前已经发现了一种新的心内膜炎致病细菌和人类纤维连接蛋白相互作用的模式。目前的研究集中在发现抑制微生物和纤维连接蛋白之间的联系的候选化合物。构建了含有N-末端生物素化6-聚肽的定位扫描文库(PSL)，并筛选其与抑制细菌FN结合的FN的单抗结合。从这些实验中得到的共识序列预计是对参与细菌黏附的纤维连接蛋白局部结构的结构模拟。由于单个人工合成的6-聚肽没有表现出预期的作用，因此可以设想不连续的表位，因此构建了一个9-聚PSL来揭示构象表位。在第二个文库中，在筛选的基础上合成了几个9聚体多肽，并给出了改进的结果。

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.