Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacterium responsible for a range of severe infections, such as skin infections, bacteremia, and pneumonia. Due to its antibiotic-resistant nature, current research focuses on targeting its virulence factors. Sortase A (SrtA) is a transpeptidase that anchors surface proteins to the bacterial cell wall and is involved in adhesion and invasion to host cells. Through fluorescence resonance energy transfer (FRET), we identified echinacoside (ECH), a natural polyphenol, as a potential SrtA inhibitor with an IC₅₀ of 38.42 μM in vitro. It was demonstrated that ECH inhibited SrtA-mediated S. aureus fibrinogen binding, surface protein A anchoring, and biofilm formation. The fluorescence quenching assay determined the binding mode of ECH to SrtA and calculated the K_A-binding constant of 3.09 × 10⁵ L/mol, demonstrating the direct interaction between the two molecules. Molecular dynamics simulations revealed that ECH–SrtA interactions occurred primarily at the binding sites of A92G, A104G, V168A, G192A, and R197A. Importantly, the combination of ECH and vancomycin offered protection against murine models of MRSA-induced pneumonia. Therefore, ECH may serve as a potential antivirulence agent against S. aureus infections, either alone or in combination with vancomycin.

耐甲氧西林金黄色葡萄球菌(MRSA) 是一种致病菌，可导致一系列严重感染，例如皮肤感染、菌血症和肺炎。由于其抗生素耐药性，目前的研究重点是针对其毒力因子。分选酶 A (SrtA) 是一种转肽酶，可将表面蛋白锚定在细菌细胞壁上，并参与对宿主细胞的粘附和侵袭。通过荧光共振能量转移 (FRET)，我们鉴定出一种天然多酚松果菊苷 (ECH) 作为潜在的 SrtA 抑制剂，体外IC _{50为 38.42 μM。}结果表明，ECH 抑制 SrtA 介导的金黄色葡萄球菌纤维蛋白原结合、表面蛋白 A 锚定和生物膜形成。荧光猝灭测定确定了ECH与SrtA的结合模式，并计算出K _A结合常数为3.09 × 10 ⁵  L/mol，证明了两个分子之间的直接相互作用。分子动力学模拟表明，ECH-SrtA 相互作用主要发生在 A92G、A104G、V168A、G192A 和 R197A 的结合位点。重要的是，ECH 和万古霉素的组合可以针对 MRSA 诱导的肺炎小鼠模型提供保护。因此，ECH 可以作为一种潜在的抗金黄色葡萄球菌感染的抗毒剂，无论是单独使用还是与万古霉素联合使用。