Rhein restores the sensitivity of mcr-1 carrying multidrug-resistant Escherichia coli to colistin

The emergence of the colistin resistance gene <i>mcr-1</i> has resulted in a significant reduction in the clinical efficacy of colistin against infections caused by multidrug-resistant Gram-negative pathogens. A cost-effective approach for restoring the efficacy of antibiotics is to formulate synergistic antibiotic combinations with natural compounds that target the resistance of multidrug-resistant bacteria. In this study, we have demonstrated that rhein can effectively restore the sensitivity of <i>mcr-1</i>-positive <i>Escherichia coli</i> to colistin, both <i>in vitro</i> and <i>in vivo</i>. Mechanism studies have demonstrated that rhein primarily damages bacterial cell membranes, disrupts proton motive force, and generates excessive reactive oxygen species, and down-regulates the <i>mcr-1</i> gene in <i>E. coli</i>. Compared to monotherapy, the combination of rhein and colistin greatly increased the survival rate of <i>E. coli</i> infected mice and significantly reduced the bacterial load in the viscera of the mice. Our results confirm that rhein serves as a promising adjuvant to colistin and, in combination with colistin, provides a viable approach to combat infections caused by colistin resistant <i>E. coli</i>.