Abstract

Staphylocoagulase (Coa) is a virulence factor of Staphylococcus aureus (S. aureus) that promotes blood coagulation by activating prothrombin to convert fibrinogen to fibrin. Coa plays a crucial role in disease pathogenesis and is a promising target for the treatment of S. aureus infections. Here, we identified that isoquercitrin, a natural flavonol compound, can markedly reduce the activity of Coa at concentrations that have no effect on bacterial growth. Mechanistic studies employing molecular dynamics simulation revealed that isoquercitrin binds to Coa by interacting with Asp-181 and Tyr-188, thereby affecting the binding of Coa to prothrombin. Importantly, in vivo studies showed that isoquercitrin treatment significantly reduced the bacterial burden, pathological damage, and inflammation of lung tissue and improved the percentage of survival of mice infected with S. aureus Newman strain. These data suggest that isoquercitrin is a promising inhibitor of Coa that can be used for the development of therapeutic drugs to combat S. aureus infections.

Key Points • Staphylocoagulase plays a key role in the pathogenesis of S. aureus infection. • We identified that isoquercitrin is a direct inhibitor of staphylocoagulase. • Isoquercitrin treatment can significantly attenuate S. aureus virulence in vivo.

中文翻译：

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用异槲皮苷靶向葡萄球菌凝固酶可保护小鼠免受金黄色葡萄球菌引起的肺炎

摘要

葡萄球菌凝固酶(Coa) 是金黄色葡萄球菌( S. aureus )的毒力因子，通过激活凝血酶原将纤维蛋白原转化为纤维蛋白来促进血液凝固。Coa 在疾病发病机制中起着至关重要的作用，是治疗金黄色葡萄球菌的有希望的靶点感染。在这里，我们发现异槲皮苷是一种天然黄酮醇化合物，可以在对细菌生长没有影响的浓度下显着降低 Coa 的活性。采用分子动力学模拟的机理研究表明，异槲皮苷通过与 Asp-181 和 Tyr-188 相互作用与 Coa 结合，从而影响 Coa 与凝血酶原的结合。重要的是，体内研究表明，异槲皮苷治疗显着减少了细菌负担、病理损伤和肺组织炎症，并提高了感染金黄色葡萄球菌纽曼菌株的小鼠的存活率。这些数据表明异槲皮苷是一种很有前途的 Coa 抑制剂，可用于开发治疗金黄色葡萄球菌感染的治疗药物。

关键点 •葡萄球菌凝固酶在金黄色葡萄球菌感染的发病机制中起关键作用。 • 我们发现异槲皮苷是葡萄球菌凝固酶的直接抑制剂。 • 异槲皮苷处理可显着减弱体内金黄色葡萄球菌的毒力。