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

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00421-6.