Glabridin restore the sensitivity of colistin against mcr-1-positive Escherichia coli by polypharmacology mechanism

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. In this study, we demonstrated that glabridin can restore the sensitivity of colistin to mcr-1-positive Escherichia coli (E. coli) and exhibits a reduced propensity for resistance development. Our investigation into the underlying mechanisms revealed that glabridin may re-sensitize E. coli to colistin by targeting MCR-1 to inhibit its activity, regulating the expression of mcr-1, and restoring the Zeta potential at the cell membrane surface. Furthermore, the combination of glabridin and colistin increased bacterial membrane permeability, decreased membrane fluidity, disrupted transmembrane proton motive force (PMF), reduced the ratios of NAD⁺/NADH and FAD/FADH₂, facilitated the tricarboxylic acid (TCA) cycle, and led to the accumulation of reactive oxygen species (ROS) in E. coli cells, ultimately resulting in bacterial death. In animal models, glabridin significantly enhanced the efficacy of colistin in treating E. coli infections. Our findings suggest that glabridin is a promising polypharmacological antibiotic adjuvant for addressing infections associated with colistin-resistant E. coli.