A novel brominated chalcone derivative as a promising multi-target inhibitor against multidrug-resistant Listeria monocytogenes.

Foodborne pathogens continue to challenge public health due to their ability to cause severe illness and their increasing resistance to current antimicrobial treatments. Listeria monocytogenes is a resilient foodborne pathogen that poses significant risks to vulnerable populations, leading to severe infections and high hospitalization rates. The emergence of antimicrobial-resistant (AMR) strains of L. monocytogenes underscores the need for novel therapeutic strategies. In this study, we investigated the antimicrobial efficacy of the (2E)-3-(3,5-dibromo-2-hydroxylphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one (DK06) against multidrug-resistant L. monocytogenes. DK06 exhibited a significant dose-dependent inhibition of L. monocytogenes growth, achieving a maximum inhibition of 92.9 % at 320 μM. Molecular docking and dynamics simulations revealed high binding affinities for key virulence proteins PlcB and ArgA, with stable protein-ligand interactions. DK06 also disrupted biofilm formation at sub-MIC levels, reducing extracellular polymeric substances (EPS) and biofilm mass, as observed by scanning electron microscopy (SEM) analysis. Furthermore, DK06 downregulated the expression of virulence genes (plcB, argA, and hly) and decreased hemolytic activity. In vivo zebrafish studies confirmed the safety of DK06 up to 80 μM, demonstrating its efficacy in reducing mortality and oxidative stress associated with L. monocytogenes infection. DK06 also attenuated inflammation by downregulating key inflammatory markers (tnfa, il1b, il6, and nfkb). These findings indicate that DK06 is a promising multi-target inhibitor with potential application in treating infections and combating antimicrobial resistance.