Baicalin Protects Mice From Staphylococcus aureus Pneumonia Via Inhibition of the Cytolytic Activity of α-Hemolysin
Baicalin Protects Mice From Staphylococcus aureus Pneumonia Via Inhibition of the Cytolytic Activity of α-Hemolysin
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DOI：
10.1093/infdis/jis336
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发表时间：
2012-07-15
影响因子：
6.4
通讯作者：
Deng, Xuming
中科院分区：
文献类型：
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作者：
Qiu, Jiazhang;Niu, Xiaodi;Deng, Xuming
-溶血素（Hla）是由金黄色葡萄球菌分泌的一种自组装、形成通道的毒素，是动物模型中肺部、腹腔、乳腺和角膜感染发病机制的核心。在本研究中，我们报道了黄芩苷（BAI），一种缺乏抗s的天然化合物。金黄色葡萄球菌活性，能抑制Hla的溶血活性。通过分子动力学模拟和诱变实验，我们进一步证明BAI与Hla中Y148、P151和F153的结合位点结合。这种结合相互作用抑制七聚体的形成。此外，当添加到金黄色葡萄球菌培养物中时，BAI可以防止hla介导的人肺泡上皮（A549）细胞损伤。体内研究进一步证明BAI可保护小鼠免受金黄色葡萄球菌肺炎。这些发现表明，BAI通过阻断七聚体形成的新机制阻碍了Hla的细胞裂解活性，这可能导致针对金黄色葡萄球菌Hla的新疗法的发展。
alpha -Hemolysin (Hla) is a self-assembling, channel-forming toxin that is secreted by Staphylococcus aureus and is central to the pathogenesis of pulmonary, intraperitoneal, intramammary, and corneal infections in animal models. In this study, we report that baicalin (BAI), a natural compound that lacks anti-S. aureus activity, could inhibit the hemolytic activity of Hla. Using molecular dynamics simulations and mutagenesis assays, we further demonstrate that BAI binds to the binding sites of Y148, P151, and F153 in the Hla. This binding interaction inhibits heptamer formation. Furthermore, when added to S. aureus cultures, BAI prevents Hla-mediated human alveolar epithelial (A549) cell injury. In vivo studies further demonstrated that BAI protects mice from S. aureus pneumonia. These findings indicate that BAI hinders the cell lysis activity of Hla through a novel mechanism of interrupting the formation of heptamer, which may lead to the development of novel therapeutics that aim against S. aureus Hla.