College of Animal Science, Jilin University, Changchun China.
Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
Virulence. 2021 Dec;12(1):2149-2161. doi: 10.1080/21505594.2021.1962138.
Drug-resistant pathogenic () has severely threatened human health and arouses widespread concern. Sortase A (SrtA) is an essential virulence factor of , which is responsible for the covalent anchoring of a variety of virulence-related proteins to the cell wall. SrtA has always been regarded as an ideal pharmacological target against infections. In this research, we have determined that orientin, a natural compound isolated from various medicinal plants, can effectively inhibit the activity of SrtA with an IC of 50.44 ± 0.51 µM. We further demonstrated that orientin inhibited the binding of to fibrinogen and diminished biofilm formation and the attaching of Staphylococcal protein A (SpA) to the cell wall . Using the fluorescence quenching assay, we demonstrated a direct interaction between orientin and SrtA. Further mechanistic studies revealed that the residues Glu-105, Thr-93, and Cys-184 were the key sites for the binding of SrtA to orientin. Importantly, we demonstrated that treatment with orientin attenuated virulence of and protected mice against -induced lethal pneumonia. These findings indicate that orientin is a potential drug to counter infections and limit the development of drug resistance.
耐药性病原菌 () 严重威胁人类健康，引起广泛关注。Sortase A (SrtA) 是 的一种重要毒力因子，负责将各种与毒力相关的蛋白质共价锚定到细胞壁上。SrtA 一直被视为针对 感染的理想药物靶点。在这项研究中，我们确定从各种药用植物中分离出的天然化合物Orientin 可以有效抑制 SrtA 的活性，IC 为 50.44 ± 0.51 µM。我们进一步证明 Orientin 抑制了 与纤维蛋白原的结合，减少了生物膜的形成和葡萄球菌蛋白 A (SpA) 与细胞壁的附着。通过荧光猝灭实验，我们证明了 Orientin 与 SrtA 之间存在直接相互作用。进一步的机制研究表明，Glu-105、Thr-93 和 Cys-184 残基是 SrtA 与 Orientin 结合的关键位点。重要的是，我们证明 Orientin 处理可以减弱 毒力并保护小鼠免受 - 诱导的致命性肺炎。这些发现表明 Orientin 是一种潜在的药物，可以对抗 感染并限制耐药性的发展。
