An integrative computational and experimental evaluation of natural compounds with potential to target LuxS in Klebsiella pneumoniae

Klebsiella pneumoniae ( KPn ) has emerged as a major global health concern due to increasing antimicrobial resistance (AMR). The development of new antimicrobial agents is essential to address multidrug-resistant and emerging hypervirulent strains associated with increased morbidity and mortality worldwide. In this study, an integrative computational–experimental approach was employed to characterise the anti-quorum sensing and anti-biofilm activities of selected natural compounds targeting the LuxS/autoinducer-2 (AI-2) system in KPn . Six compounds were initially screened using homology modelling, molecular docking, pharmacophore analysis, and molecular dynamics (MD) simulations. Resveratrol, quercetin, and epigallocatechin gallate showed favourable binding to LuxS. Although quercetin (ΔG_bind = − 45.47 kcal/mol) and epigallocatechin gallate (− 43.04 kcal/mol) exhibited stronger predicted affinities than resveratrol (− 39.22 kcal/mol), resveratrol demonstrated superior complex stability (RMSD: 1.8 ± 0.2 Å) and persistent interactions with key residues (Tyr63, Trp68). Experimental validation demonstrated that resveratrol exhibited significant antimicrobial activity (MIC/MBC = 32 µg/mL), significantly inhibited quorum sensing-associated phenotypes, and reduced KPn - Acinetobacter baumannii ( ABa ) dual-species biofilm formation inhibition by 54.7%. These findings identify resveratrol as a promising anti-virulence candidate and highlight the utility of integrative computational and experimental strategies for the identification of compounds targeting quorum sensing and biofilm formation inhibition in multidrug-resistant pathogens. Graphical abstract showing natural compounds investigated in this study and their interaction with the LuxS protein, a key regulator of quorum sensing in Klebsiella pneumoniae