Baicalin Weakens Staphylococcus aureus Pathogenicity by Targeting Sortase B
Baicalin Weakens Staphylococcus aureus Pathogenicity by Targeting Sortase B
复制标题
黄芩苷通过靶向分选酶 B 减弱金黄色葡萄球菌的致病性
DOI：
10.3389/fcimb.2018.00418
复制
发表时间：
2018-11-30
影响因子：
5.7
通讯作者：
Wang, Jianfeng
中科院分区：
文献类型：
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作者：
Wang, Guizhen;Gao, Yawen;Wang, Jianfeng
金黄色葡萄球菌(S.aureus)是一种人类和其他动物的病原体，是医院获得性肺炎的主要病原体，是一种死亡率高、成本高的疾病。多药耐药金黄色葡萄球菌感染的治疗极具挑战性，需要在抗生素治疗之外的新的治疗策略。针对毒力分子决定因素的抗毒力药物可能是治疗耐药医院感染的一种新方法。山梨酸酶B(Sortase B，SrtB)是金黄色葡萄球菌的重要毒力因子，在感染过程中起着重要作用。在本研究中，我们发现黄芩苷对srtB活性有抑制作用。经最低抑菌浓度和生长曲线测定证实，黄芩苷没有抗S。金色属性。我们进行了活/死、乳酸脱氢酶(LDH)、黏附和酶联免疫吸附试验，证实黄芩苷可减轻金黄色葡萄球菌对人肺泡上皮细胞A549的损伤，减少金黄色葡萄球菌对A549细胞的黏附，并显著减轻小鼠巨噬细胞J774对金黄色葡萄球菌的炎症反应。此外，我们还通过分子动力学模拟、定点突变和荧光光谱猝灭，阐明了黄芩苷和SrtB的结合机理和相互作用部位。最后，我们证实黄芩苷直接与SrtB的活性中心结合，残基Asn92和Tyr128在SrtB与黄芩苷的相互作用中起着重要的作用。综上所述，这些数据表明，黄芩苷是一个很有希望的候选药物来对抗金黄色葡萄球菌感染。
Staphylococcus aureus (S. aureus) is a human and other animal pathogen that contributes to the primary etiology of nosocomial pneumonia, a disease with high mortality rates and costs. Treatment of multidrug-resistant S. aureus infection is extremely challenging, and new therapeutic strategies beyond antibiotic treatment are needed. Anti-virulence agents that specifically target the molecular determinants of virulence may be a novel method for treating drug-resistant nosocomial infections. Sortase B (SrtB) is a crucial virulence factor in S. aureus and plays an important role during infection. In this study, we find that baicalin suppresses the activity of SrtB. Minimum inhibitory concentration and growth curve assays confirmed that baicalin has no anti-S. aureus properties. We performed live/dead, lactate dehydrogenase (LDH), adherence, and enzyme-linked immunosorbent assays to confirm that baicalin reduced human alveolar epithelial A549 cell injury caused by S. aureus, reduced the adherence of S. aureus to A549 cells, and significantly attenuated the inflammatory response of mouse macrophage J774 cells to S. aureus. Additionally, we were able to elucidate the binding mechanics and identify the interacting sites of baicalin and SrtB via a molecular dynamics simulation, site-directed mutagenesis, and fluorescence spectroscopy quenching. Finally, we confirmed that baicalin directly binds to the active center of SrtB, and the residues Asn92 and Tyr128 perform an important function in the interaction of SrtB and baicalin. Taken together, these data indicate that baicalin is a promising candidate to combat S. aureus infections.