EUGENOL AS A SYNERGISTIC ADJUVANT TO CONVENTIONAL ANTIBIOTICS AGAINST MULTIDRUG-RESISTANT Klebsiella pneumoniae: AN INTEGRATED in vitro AND QUANTUM-BASED in silico APPROACH.

Abstract

The escalating antimicrobial resistance of Klebsiella pneumoniae poses a critical public health challenge, demanding innovative therapeutic strategies. This study investigated the antibacterial activity of eugenol (EOL) and its potential as a resistance-modulating agent when combined with conventional antibiotics-amoxicillin (AXL), azithromycin (AZT), cephalexin (CEF), and ciprofloxacin (CIP)-against clinical multidrug-resistant isolates. EOL exhibited intrinsic antibacterial activity with MIC values ranging from 1024 to 2048 μg/mL. Checkerboard assays revealed synergistic interactions between EOL and AXL or AZT (FICI ≤ 0.5), while combinations with CEF and CIP were indifferent. These synergistic effects were corroborated by growth inhibition curves, time-kill kinetics, and biofilm suppression assays, all of which demonstrated a marked reduction in bacterial viability and biofilm formation. Molecular docking and quantum mechanical calculations further elucidated the enhanced binding affinities and intermolecular interactions between AXL-EOL complexes and key resistance-related targets (KPC, LpxC, and particularly the quorum-sensing regulator SdiA), with interaction energies reaching up to -52.06 kcal/mol. Altogether, the findings underscore the potential of EOL as a potent adjuvant that augments the efficacy of conventional antibiotics, offering a promising pathway toward the development of targeted therapies against multidrug-resistant K. pneumoniae.