Sorbose metabolism promotes fitness and virulence in Escherichia coli.

The plasmid-borne mcr-1 gene poses a significant threat to global health by conferring resistance to colistin, a critical last-resort antibiotic. While its spread is well documented, the adaptations enabling its concurrent antibiotic resistance and clinical pathogenicity remain unknown. The metabolism of bacterial pathogens has evolved to support virulence in nutrient-limiting host environments. Here, we show that sorbose metabolism promotes the fitness and virulence of mcr-1-positive Escherichia coli (MCRPEC), but does not affect its resistance to colistin or polymyxin B. Notably, the virulence contribution is also observed in an mcr-1-negative background. Genetic disruption of sorbose catabolism (ΔsorD) attenuated MCRPEC virulence and fitness both in vitro and in vivo. Integrated transcriptomic and metabolomic analyses suggest that this attenuation is associated with impaired expression of two major virulence determinants. First, defective sorbose metabolism limits the supply of monosaccharide precursors required for LPS biosynthesis, leading to reduced LPS content. Second, metabolic disruption decreases intracellular cAMP levels, which downregulates fimH expression via a cAMP-dependent signaling pathway, thereby compromising bacterial adhesion. Notably, although sorD deletion enhances biofilm formation, this increase is insufficient to rescue the in vivo virulence defect. Restoration of the sorbose metabolic pathway partially rescues MCRPEC pathogenicity. These findings suggest that sorbose metabolism contributes to MCRPEC pathogenicity by supporting LPS synthesis and regulating fimH expression via cAMP signaling. This study indicates a metabolic link between sorbose utilization and MCRPEC pathogenicity, raising the possibility that sorbose, a common food additive, could facilitate MCRPEC pathogenicity.IMPORTANCEThe spread of colistin-resistant Escherichia coli (E. coli) limits treatment options for life-threatening infections. This study shows that sorbose metabolism, which utilizes a common dietary sugar, contributes to the fitness and virulence of such resistant bacteria without affecting their colistin resistance. Using mcr-1-positive E. coli, we find that this metabolic pathway supports lipopolysaccharide synthesis and, via a cAMP-dependent mechanism, promotes bacterial adhesion. Disabling sorbose catabolism attenuates the pathogen in animal models. These findings suggest a previously unrecognized link between a specific carbohydrate metabolism and pathogenesis in drug-resistant E. coli, raising the possibility that dietary components may influence infection outcomes.