STAPHYLOCOCCUS AUREUS FIBRONECTIN-BINDING ADHESINS

描述（由申请人提供）：金黄色葡萄球菌仍然是导致皮肤和深层软组织感染的主要人类病原体，可能使植入装置和手术伤口部位复杂化。对抗生素耐药的葡萄球菌菌株的日益流行对患者和公众健康构成威胁。需要新的预防和治疗方法来对抗这种病原体。由于葡萄球菌对宿主组织的粘附对于定植和感染至关重要，因此葡萄球菌表面蛋白可能是细菌和宿主之间的第一个接触点，因此是重要的预防目标。在与宿主结构结合的葡萄球菌表面蛋白中，纤连蛋白结合蛋白 (FnBP) 是主要的纤连蛋白 (Fn) 结合粘附，介导体外细菌粘附和细胞内侵袭。最近的一项研究证实了 FnBP 在心内膜炎模型感染启动中的重要性。不幸的是，大多数使用 FnBP 作为疫苗靶点的尝试都因抗 FnBP 抗体的阻断能力差而受到阻碍。在非疫苗方法中，金黄色葡萄球菌的 FnBP 片段已被用于预防豚鼠模型中伤口感染的发生。 FnBP 这种作用模式的一种解释是，它竞争性地阻断葡萄球菌与宿主靶标（例如 Fn 和/或其他受体）的结合。鉴于几乎所有葡萄球菌菌株都具有结合 Fn 的能力，该 FnBP 片段在伤口感染预防中的预防作用可能广泛适用于大多数金黄色葡萄球菌菌株。使用重组和合成 FnBP 构建体对 FnBP 分子进行的先前研究的观察结果将应用于伤口感染模型，以努力确定 FnBP 内负责该动物模型预防作用的关键区域。此外，还将检查可能对 FnBP 的预防作用有效的抗粘连和/或炎症机制。 FnBP 作为抗粘附素的使用为预防金黄色葡萄球菌感染提供了一种新的治疗工具。

DESCRIPTION (provided by applicant): Staphylococcus aureus continues to be a major human pathogen causing skin and deep soft-tissue infections that may complicate implanted devices and surgical wound sites. The increasing prevalence of staphylococcal strains that are resistant to antibiotics looms as a threat to patients and the public health. Novel preventive and therapeutic approaches are needed for combating this pathogen. Since adherence of staphylococci to host tissues is critical for colonization and infection, staphylococcal surface proteins are likely to be the first point of contact between the bacterium and the host and, thus, are important preventive targets. Of the staphylococcal surface proteins that bind to host structures, the fibronectin-binding proteins (FnBP) are the major fibronectin (Fn)-binding adhesions and mediate bacterial adherence and intracellular invasion in vitro. A recent study has confirmed the importance of FnBP in the initiation of infection in an endocarditis model. Unfortunately, most attempts to use FnBP as a vaccine target have been hampered by poor blocking capacity of anti-FnBP antibodies. In a non-vaccine approach, a fragment of the FnBP of S. aureus has been used to prevent the establishment of wound infection in a guinea pig model. One explanation of this mode of action of FnBP is that it competitively blocks the binding of staphylococci to host targets such as Fn and/or other receptors. The preventive effects of this FnBP fragment In wound infection prophylaxis are likely broadly applicable to most S. aureus strains given that the capacity to bind Fn is common for almost all staphylococcal strains. Observations from prior studies of the FnBP molecule using recombinant and synthetic FnBP constructs will be applied to the wound infection model in an effort to identify critical regions within FnBP that are responsible for the preventive effect in this animal model. Also, anti-adhesive and/or inflammatory mechanisms that may be operative in the preventive effect of FnBP will be examined. The use of FnBP as an anti-adhesin presents a novel therapeutic tool for the prevention of S. aureus infections.