SoxR-targeted redox vulnerability enables zinc-vitamin K3 therapy against Escherichia coli infection

The rapid emergence of multidrug-resistant Escherichia coli highlights the urgent need for effective, host-compatible antibacterial strategies. Targeting bacterial redox homeostasis represents a promising non-antibiotic paradigm, yet rational synergistic approaches remain poorly defined. We show that zinc combined with vitamin K3 exhibits potent antibacterial activity against pathogenic E. coli , including enterotoxigenic ETEC K88, by selectively disrupting redox regulation. Mechanistically, Zn²⁺ targets the redox-sensitive transcription factor SoxR, inactivating the SoxR-SoxS pathway and suppressing the downstream superoxide dismutase (SOD) antioxidative axis, thereby impairing the bacterial adaptive response to oxidative stress and rendering the pathogen highly susceptible to oxidative damage. This effect is further amplified by vitamin K3-mediated superoxide generation, resulting in synergistic bactericidal activity. In the present study, the Zn²⁺-vitamin K3 combination was validated across multiple infection models, including in vitro systems, a Galleria mellonella infection model, and an ETEC K88-induced murine diarrhea model, where it reduced bacterial burden, improved host survival, and alleviated intestinal pathology. Importantly, gut microbiota analysis revealed partial restoration of infection-associated dysbiosis without broad microbial depletion. These findings establish redox homeostasis disruption as a microbiota compatible antibacterial strategy against multidrug-resistant E. coli .