异牡荆苷作为sortase A抑制剂对小鼠金黄色葡萄球菌肺炎的保护作用

Isovitexin as an inhibitor of sortase A protects mice from Staphylococcus aureus pneumonia

sortase A(SrtA)是一种重要的毒力决定因子,负责将多种毒力相关蛋白锚定在金黄色葡萄球菌(S.aureus)的细胞表面,在其致病过程中发挥重要作用,是开发抗金黄色葡萄球菌毒力药物的理想靶点。本研究首先通过荧光共振能量转移试验发现异牡荆苷是SrtA的可逆抑制剂;又利用细胞侵袭试验证明异牡荆苷能够显著抑制金黄色葡萄球菌对A549细胞的内化作用;最后考察了异牡荆苷对小鼠肺炎的保护作用,发现异牡荆苷能明显减轻金黄色葡萄球菌感染性肺炎小鼠肺组织的病理损伤和炎症反应,减少肺部载菌量,显著提高小鼠存活率。以上结果表明,异牡荆苷能够通过抑制毒力因子SrtA对金黄色葡萄球菌引起的小鼠肺炎起到保护作用,是一种很有前景的抗金黄色葡萄球菌毒力活性化合物,可作为开发治疗金黄色葡萄球菌感染药物的先导化合物。

Sortase A(SrtA)is an important virulence determinant which is responsible for anchoring multiple virulence-related proteins on the cell wall.The vital role of SrtA in the pathogenicity of S.aureus makes it an ideal druggable target for the development of anti-virulence agents against S.aureus infection.Fluorescence resonance energy transfer experiments proved that isovitexin is an inhibitor of SrtA in vitro.Further results showed that isovitexin reversibly inhibited SrtA activity without affecting the expression of SrtA protein.Treatment with isovitexin significantly inhibited S.aureus invasion into A549 cells.Finally,we investigated the protective effect of isovitexin on pneumonia in mice,demonstrating that treatment with isovitexin alleviated the pathological injury and inflammation of lung tissue,decreased the lung bacterial burden and increased the survival rate in a murine model of S.aureus pneumonia.The above results indicated that isovitexin can exert a protective effect against pneumonia caused by S.aureus in mice by inhibiting the virulence factor SrtA,and it is a promising anti-virulence active compound that can be used as a lead compound for the development of drugs to treat S.aureus infection.