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A non-beta-lactam antibiotic inhibitor for enterohemorrhagic Escherichia coli O104:H4

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Abstract

The overuse of antibiotics has caused an increased prevalence of drug-resistant bacteria. Bacterial resistance in E. coli is regulated via production of β-lactam-hydrolyzing β-lactamases enzymes. Escherichia coli O104: H4 is a multi-drug resistant strain known to resist β-lactam as well as several other antibiotics. Here, we report a molecular dynamic simulation–combined docking approach to identify, screen, and verify active pharmacophores against enterohemorrhagic Escherichia coli (EHEC). Experimental studies revealed a boronic acid cyclic monomer (BACM), a non-β-lactam compound, to inhibit the growth of E. coli O104: H4. In vitro Kirby Bauer disk diffusion susceptibility testing coupled interaction analysis suggests BACM inhibits E. coli O104:H4 growth by not only inhibiting the β-lactamase pathway but also via direct inhibition of the penicillin-binding protein. These results suggest that BACM could be used as a lead compound to develop potent drugs targeting beta-lactam resistant Gram-negative bacterial strains.

Key messages

• An in silico approach was reported to identify pharmacophores against E. coli O104: H4.

• In vitro studies revealed a non-β-lactam compound to inhibit the growth of E. coli O104: H4.

• This non-β-lactam compound could be used as a lead compound for targeting beta-lactam strains.

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Acknowledgments

Partial support from the Ray Nesbitt Chair endowment to AJ is acknowledged.

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Authors and Affiliations

  1. Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX, USA

    Haoqi Wang, Varun Gejji & Sandun Fernando

  2. Department of Chemical Engineering, Texas A&M University, College Station, TX, USA

    Arul Jayaraman & Rani Menon

  3. Consulting Engineer, College Station, TX, USA

    R. Karthikeyan

Authors
  1. Haoqi Wang
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  2. Arul Jayaraman
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  4. Varun Gejji
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  5. R. Karthikeyan
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Contributions

Wang conducted molecular dynamics simulations, experimental studies, and compiled the manuscript. Jayaraman and Menon helped conduct the experimental studies. Karthikeyan and Gejji helped set up the experiments and Fernando directed molecular dynamics simulation algorithm development and the overall study.

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Correspondence to Sandun Fernando.

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Wang, H., Jayaraman, A., Menon, R. et al. A non-beta-lactam antibiotic inhibitor for enterohemorrhagic Escherichia coli O104:H4. J Mol Med 97, 1285–1297 (2019). https://doi.org/10.1007/s00109-019-01803-y

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  • DOI: https://doi.org/10.1007/s00109-019-01803-y

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