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<p>The global dissemination of extended-spectrum β-lactamases (ESBLs) represents an urgent public health challenge. This study employed a drug repurposing strategy integrating in-silico screening, molecular dynamics (MD) simulations, and in-vitro validation to identify FDA-approved compounds capable of potentiating β-lactam antibiotics against ESBL-producing bacteria. Structure-based virtual screening of 400 FDA-approved compounds against SHV-1 β-lactamase (PDB: 4ZAM) identified 28 compounds with promising binding energies. Four commercially available compounds; epinephrine, omeprazole, sulfadimethoxine, and captopril exhibited binding energies ranging from − 8.15 to − 9.58&#xa0;kcal/mol with RMSD values of 1.5–2.3 Å, comparable to the reference inhibitor avibactam. MD simulations (250 ns) confirmed the stability of all protein–ligand complexes, with the SHV-1/epinephrine complex demonstrating the lowest RMSD (0.155&#xa0;nm) and most compact structure. In-vitro evaluation against an ESBL-producing <i>Escherichia coli</i> clinical isolate revealed that epinephrine and omeprazole effectively enhanced antibiotic activity in disk diffusion assays. The ceftriaxone/omeprazole combination achieved the highest potentiation (20&#xa0;mm at 250&#xa0;µg/mL), followed by ceftriaxone/epinephrine (18&#xa0;mm at 250&#xa0;µg/mL) and cefuroxime/omeprazole (19&#xa0;mm at 125&#xa0;µg/mL). Notably, captopril showed no in-vitro activity despite favorable computational predictions, underscoring the importance of experimental validation in drug discovery. These findings highlight the potential of epinephrine and omeprazole as readily available adjuvants against Class A serine β-lactamases, offering a cost-effective strategy to combat ESBL-mediated antibiotic resistance.</p>

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Synergistic Potential of Repurposing non-β-lactam Compounds as Class A serine β-lactamases Inhibitor: Insights from MolecularDocking, Molecular Dynamics Simulations and Antimicrobial Potentiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月10日

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  • Mohammed Sulieman Abdalla,
  • Somenath Dutta,
  • Mujtba Osman Sulieman,
  • Arif Adil Jaber,
  • Mohammed Osman Noorelhuda,
  • Omer Fathelrahman Elkhidir,
  • Sudipta Sardar,
  • Nooh Mohamed Hajhamed,
  • Talal A. Awad,
  • Sufyan Awdelkarim Mustafa,
  • Sun-Gu Lee,
  • Najem Aldin M. Aldin

摘要

The global dissemination of extended-spectrum β-lactamases (ESBLs) represents an urgent public health challenge. This study employed a drug repurposing strategy integrating in-silico screening, molecular dynamics (MD) simulations, and in-vitro validation to identify FDA-approved compounds capable of potentiating β-lactam antibiotics against ESBL-producing bacteria. Structure-based virtual screening of 400 FDA-approved compounds against SHV-1 β-lactamase (PDB: 4ZAM) identified 28 compounds with promising binding energies. Four commercially available compounds; epinephrine, omeprazole, sulfadimethoxine, and captopril exhibited binding energies ranging from − 8.15 to − 9.58 kcal/mol with RMSD values of 1.5–2.3 Å, comparable to the reference inhibitor avibactam. MD simulations (250 ns) confirmed the stability of all protein–ligand complexes, with the SHV-1/epinephrine complex demonstrating the lowest RMSD (0.155 nm) and most compact structure. In-vitro evaluation against an ESBL-producing Escherichia coli clinical isolate revealed that epinephrine and omeprazole effectively enhanced antibiotic activity in disk diffusion assays. The ceftriaxone/omeprazole combination achieved the highest potentiation (20 mm at 250 µg/mL), followed by ceftriaxone/epinephrine (18 mm at 250 µg/mL) and cefuroxime/omeprazole (19 mm at 125 µg/mL). Notably, captopril showed no in-vitro activity despite favorable computational predictions, underscoring the importance of experimental validation in drug discovery. These findings highlight the potential of epinephrine and omeprazole as readily available adjuvants against Class A serine β-lactamases, offering a cost-effective strategy to combat ESBL-mediated antibiotic resistance.