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首页> 外文期刊>Biochemical Pharmacology >Baicalein mediates protection against Staphylococcus aureus-induced pneumonia by inhibiting the coagulase activity of vWbp
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Baicalein mediates protection against Staphylococcus aureus-induced pneumonia by inhibiting the coagulase activity of vWbp

机译：Baicalein通过抑制VWBP的凝固酶活性来介导对金黄色葡萄球菌诱导的肺炎的保护

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摘要

The emergence and spread of multidrug-resistant Staphylococcus aureus (S. aureus) necessitate the research on therapeutic tactics which are different from classical antibiotics in overcoming resistance and treating infections. In S. aureus, von Willebrand factor-binding protein (vWbp) is one of the key virulence determinants because it mediates not only the activation of thrombin to convert fibrinogen to fibrin, thereby enabling S. aureus to escape from the host immune clearance, but also the adhesion of S. aureus to host cells. Thus, vWbp is regarded as a promising druggable target to treat S. aureus-associated infections. Here we identify that baicalein, a natural compound isolated from the Chinese herb Scutellaria baicalensis, can effectively block the coagulase activity of vWbp without inhibiting the growth of the bacteria. Through thermal shift and fluorescence quenching assays, we demonstrated that baicalein directly binds to vWbp. Molecular dynamics simulations and mutagenesis assays revealed that the Asp-75 and Lys-80 residues are necessary for baicalein binding to vWbp. Importantly, we demonstrated that baicalein treatment attenuates the virulence of S. aureus and protects mice from S. aureus-induced lethal pneumonia. In addition, baicalein can improve the therapeutic effect of penicillin G by 75% in vivo. These findings indicate that baicalein might be developed as a promising therapeutic agent against drug-resistant S. aureus infections.
机译：多药抗性金黄色葡萄球菌的出现和传播（S. aureus）需要研究与克服耐药性和治疗感染的古典抗生素不同的治疗策略。在S.金黄色葡萄球菌中，Von Willebrand因子结合蛋白（VWBP）是关键毒力决定因素之一，因为它不仅介导凝血酶的激活以将纤维蛋白剂转化为纤维蛋白，从而使金黄色葡萄球菌从宿​​主免疫清除中逃逸，但是也是S. aureus对宿主细胞的粘附性。因此，VWBP被认为是治疗金黄色葡萄球菌相关的感染的有前途的可用性靶标。在这里，我们鉴定了从中国草药Scutellaria Baicalensis中分离的天然化合物，可以有效阻断VWBP的凝血酶活性而不抑制细菌的生长。通过热移位和荧光猝灭测定，我们证明了Baicalein直接与VWBP结合。分子动力学模拟和诱变测定显示，ASP-75和Lys-80残基是Baicalina与VWBP结合所必需的。重要的是，我们证明了巴氏菌治疗衰减了金黄色葡萄球菌的毒力，并保护来自金黄色葡萄球菌诱导的致死肺炎的小鼠。此外，Baicaline可以在体内提高青霉素G的治疗效果75％。这些发现表明，Baicalein可以作为抗耐药性S. aureus感染的有前途的治疗剂开发。

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