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Inhibitor discovery for the E. coli meningitis virulence factor IbeA from homology modeling and virtual screening

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Abstract

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.

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Acknowledgements

The authors thank Professor Cameron Mackereth from European institute of Chemistry and Biology, Professor Yuxing Chen and Congzhao Zhou from University of Science and Technology of China for their suggestions and polishing the manuscript.

Funding

This research was supported by grants from the National Natural Science Foundation of China (No. 31600611) and the Department of Education of Liaoning province (No. L2015594).

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Authors and Affiliations

  1. Department of Developmental Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China

    Xiaoqian Xu, Ying Cai, Dongxin Liu, Zhengwen Shang, Qiuhong Ren, Weidong Zhao & Yuhua Chen

  2. Department of Life Science, Liaoning University, Shenyang, China

    Li Zhang

  3. Department of Life Science, University of Science and Technology of China, Hefei, China

    Qiong Li

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  1. Xiaoqian Xu
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  2. Li Zhang
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Contributions

X.Q.X. and L.Z. conducted the computational experiments and analysis; Y.C., Z.W.S. and Q.H.R. carried out the cellular and bacterial assays; Q.L. performed the SPR binding ability tests; D.X.L. and W.D.Z. contributed in the experimental data arrangement and summary; X.Q.X and Y.H.C. designed the experiments and wrote the manuscript.

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Correspondence to Xiaoqian Xu or Yuhua Chen.

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Xu, X., Zhang, L., Cai, Y. et al. Inhibitor discovery for the E. coli meningitis virulence factor IbeA from homology modeling and virtual screening. J Comput Aided Mol Des 34, 11–25 (2020). https://doi.org/10.1007/s10822-019-00250-8

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