Escherichia coli (E. coli) K1 is the most common Gram-negative bacteria cause of neonatal meningitis. The penetration of E. coli through the blood-brain barrier is a key step of the meningitis pathogenesis. A host receptor protein, Caspr1, interacts with the E. coli virulence factor IbeA and thus facilitates bacterial penetration through the blood-brain barrier. Based on this result, we have now predicted the binding pattern between Caspr1 and IbeA by an integrated computational protocol. Based on the predicted model, we have identified a putative molecular binding pocket in IbeA, that directly bind with Caspr1. This evidence indicates that the IbeA (229-343aa) region might play a key role in mediating the bacteria invasion. Virtual screening with the molecular model was conducted to search for potential inhibitors from 213,279 commercially available chemical compounds. From the top 50 identified compounds, 9 demonstrated a direct binding ability to the residues within the Caspr1 binding site on IbeA. By using human brain microvascular endothelial cells (hBMEC) with E. coli strain RS218, four molecules were characterized that significantly attenuated the bacteria invasions at concentrations devoid of cell toxicity. Our study provides useful structural information for understanding the pathogenesis of neonatal meningitis, and have identified drug-like compounds that could be used to develop effective anti-meningitis agents.

中文翻译：

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通过同源性建模和虚拟筛选发现大肠杆菌脑膜炎毒力因子IbeA的抑制剂。

大肠杆菌（E. coli）K1是引起新生儿脑膜炎的最常见革兰氏阴性细菌。大肠杆菌通过血脑屏障的渗透是脑膜炎发病机制的关键步骤。宿主受体蛋白Caspr1与大肠杆菌毒力因子IbeA相互作用，从而促进细菌穿过血脑屏障的渗透。基于此结果，我们现在已经通过集成计算协议预测了Caspr1和IbeA之间的绑定模式。基于预测的模型，我们在IbeA中鉴定出一个推定的分子结合口袋，该口袋直接与Caspr1结合。该证据表明，IbeA（229-343aa）区可能在介导细菌入侵中起关键作用。用分子模型进行了虚拟筛选，以寻找213种潜在的抑制剂，279种市售化合物。在确定的前50种化合物中，有9种对IbeA上Caspr1结合位点内的残基具有直接结合能力。通过将人脑微血管内皮细胞（hBMEC）与大肠杆菌RS218结合使用，可以表征四个分子，从而在没有细胞毒性的浓度下显着减弱了细菌的入侵。我们的研究为了解新生儿脑膜炎的发病机理提供了有用的结构信息，并确定了可用于开发有效的抗脑膜炎药物的类药物化合物。四个分子的特征是在没有细胞毒性的浓度下显着减弱了细菌的入侵。我们的研究为了解新生儿脑膜炎的发病机理提供了有用的结构信息，并确定了可用于开发有效的抗脑膜炎药物的类药物化合物。四个分子的特征是在没有细胞毒性的浓度下显着减弱了细菌的入侵。我们的研究为了解新生儿脑膜炎的发病机理提供了有用的结构信息，并确定了可用于开发有效的抗脑膜炎药物的类药物化合物。