The manuscript dataset 'Glabridin restores sensitivity of colistin to mcr-1-positive Escherichia coli through multiple pharmacological mechanisms'.

The clinical effectiveness of colistin against multidrug-resistant Gram-negative pathogen infections has been threatened by the emergence of the plasmid-mediated colistin-resistant gene mcr-1. This development underscores the urgent need for innovative therapeutic strategies that target resistance mechanisms. Natural products have garnered significant interest as potential adjuvants design due to their abundant availability, minimal adverse, and varied antimicrobial mechanisms. Glabridin, a compound derived from Glycyrrhiza uralensis Fisch, was shown to surprisingly restore the susceptibility of colistin-resistant Escherichia coli (E. coli) and was less likely to develop resistance. This study aimed to elucidate the mechanism by which glabridin, in combination with colistin, exerts anti-mcr-1-positive E. coli effects. Molecular docking and cellular thermal shift assays demonstrated that glabridin directly interacts with MCR-1, inhibiting its activity and thereby exerting antimicrobial effects. Importantly, glabridin significantly downregulated the expression and translation of the mcr-1 resistance gene. Furthermore, glabridin increased bacterial membrane permeability and disrupted membrane function, thereby enhancing the membrane-disrupting effects of colistin. Concurrently, the combination of glabridin and visfatin demonstrated antimicrobial properties by enhancing the tricarboxylic acid (TCA) cycle and cellular respiration, leading to the induction of reactive oxygen species (ROS) damage. Finally, in animal models, glabridin significantly improved the efficacy of colistin in treating E. coli infections. Our experiments suggest that glabridin is an excellent polypharmacology mechanism antibiotic adjuvant for infections associated with colistin-resistant E. coli.