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<p>The rise of β-lactamase-mediated resistance in Gram-negative pathogens has created an urgent need for novel inhibitors to preserve antibiotic efficacy. This study explores the potential of curcumin, a natural polyphenol with known antimicrobial properties, as a broad-spectrum inhibitor of class A serine-β-lactamases (SBLs) through comprehensive computational analysis. Using molecular docking, 200&#xa0;ns molecular dynamics simulations, and binding energy calculations, we investigated curcumin’s interactions with three clinically important SBLs: KPC-3, CTX-M-15, and L2. Our results demonstrate curcumin’s strong binding affinity across all three enzymes, with particularly potent inhibition of L2 (ΔG = − 7.67&#xa0;kcal/mol) driven by favorable van der Waals interactions (− 115.03&#xa0;kJ/mol) and an extensive hydrogen bonding network involving catalytic residues Ser70 and Ser130. Molecular dynamics simulations revealed distinct inhibition mechanisms: L2 showed global stabilization with reduced flexibility (15–20% decrease in RMSF); CTX-M-15 exhibited balanced binding with moderate solvation effects; while KPC-3 displayed local active-site stabilization despite overall structural destabilization, evidenced by increased radius of gyration. These findings highlight curcumin’s remarkable adaptability as a multi-target β-lactamase inhibitor, capable of employing enzyme-specific strategies while maintaining core inhibitory interactions. The study provides crucial molecular insights that could guide the development of curcumin-derived adjuvants to combat β-lactam resistance, bridging traditional medicine and modern drug discovery approaches to address this critical public health challenge.</p>

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Deciphering curcumin’s differential inhibition of KPC-3, L2, and CTX-M-15 β-lactamases through binding energetics and structural dynamics

  • 期刊论文

  • 发表日期：

    2025年9月4日

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  • Rafiullah Shirzadi,
  • Abdul Musawer Bayan,
  • Sayed Hussain Mosawi

摘要

The rise of β-lactamase-mediated resistance in Gram-negative pathogens has created an urgent need for novel inhibitors to preserve antibiotic efficacy. This study explores the potential of curcumin, a natural polyphenol with known antimicrobial properties, as a broad-spectrum inhibitor of class A serine-β-lactamases (SBLs) through comprehensive computational analysis. Using molecular docking, 200 ns molecular dynamics simulations, and binding energy calculations, we investigated curcumin’s interactions with three clinically important SBLs: KPC-3, CTX-M-15, and L2. Our results demonstrate curcumin’s strong binding affinity across all three enzymes, with particularly potent inhibition of L2 (ΔG = − 7.67 kcal/mol) driven by favorable van der Waals interactions (− 115.03 kJ/mol) and an extensive hydrogen bonding network involving catalytic residues Ser70 and Ser130. Molecular dynamics simulations revealed distinct inhibition mechanisms: L2 showed global stabilization with reduced flexibility (15–20% decrease in RMSF); CTX-M-15 exhibited balanced binding with moderate solvation effects; while KPC-3 displayed local active-site stabilization despite overall structural destabilization, evidenced by increased radius of gyration. These findings highlight curcumin’s remarkable adaptability as a multi-target β-lactamase inhibitor, capable of employing enzyme-specific strategies while maintaining core inhibitory interactions. The study provides crucial molecular insights that could guide the development of curcumin-derived adjuvants to combat β-lactam resistance, bridging traditional medicine and modern drug discovery approaches to address this critical public health challenge.