Quercetin Enhances the Antibacterial Activity of Polymyxin E Against MCR-1-Positive Bacteria by Inhibiting the Biological Functions of the Cell Membrane

Simple SummaryPolymyxin E is widely considered the last resort for treating multidrug-resistant Gram-negative bacteria. However, due to the emergence of the plasmid-mediated MCR-1 resistance gene, an increasing number of strains have developed resistance to polymyxin E. Additionally, the prevalence ofEscherichia coliin chickens has imposed a heavy burden on the global food and poultry farming industries. This study aimed to investigate the in vitro and in vivo synergistic effects and mechanisms of quercetin (QUE) combined with polymyxin E against MCR-1-positiveE. coliJD37 from chickens. The in vitro and in vivo synergistic effects of QUE and polymyxin E were confirmed through in vitro drug sensitivity tests, growth curves, time-kill curves, agar diffusion tests, and in vivo chick infection experiments. The results showed that QUE restored the sensitivity of polymyxin E toE. coliJD37 and restored the sensitivity of polymyxin E toE. coliJD37 mainly by increasing the permeability of the cell membrane, elevating the fluidity of the cell membrane, increasing the membrane potential, and reducing the expression of the AcrAB-TolC efflux pump and Lipopolysaccharide (LPS) regulatory-related genes. Molecular docking results revealed the key binding sites of QUE to MCR-1.In animal husbandry and livestock farming, with the spread of the plasmid-mediated MCR-1 gene, polymyxin E, as the last line of defense against drug-resistant Gram-negative bacteria, is facing severe challenges. This study investigated the in vitro and in vivo synergistic effects and mechanisms of QUE combined with polymyxin E against MCR-1-positive chickenE. coliJD37. In vitro experiments showed that QUE could restore the sensitivity ofE. coliJD37 to polymyxin E (FIC = 0.34375) and enhance the bactericidal effect of polymyxin E by increasing cell membrane permeability, fluidity, and membrane potential, downregulating the expression of the AcrAB-TolC efflux pump and LPS-related genes. Molecular docking further identified the key residues for QUE binding to the MCR-1 protein. The in vivo chick infection model confirmed that combination therapy increased survival rates, reduced bacterial load in tissues, alleviated pathological damage, and decreased levels of intestinal inflammatory factors. Our results demonstrate the synergistic bactericidal effect of the QUE-polymyxin E combination against MCR-1-positiveE. coliand elucidate its underlying mechanism.