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Pathogenic members of the Enterobacteriaceae family, including Shigella flexneri and certain strains of Escherichia coli, are major causes of gastroenteritis worldwide. Many of their harmful effects stem from toxins such as Shiga and Shiga-like toxins. Conventional antibiotic treatment is often avoided, as it can intensify toxin-induced tissue injury and accelerate the emergence of antimicrobial resistance. The host protease furin is known to activate a variety of viral glycoproteins and bacterial toxins, thereby contributing to pathogen virulence. This study investigated whether inhibition of furin could attenuate cytotoxic effects induced by intestinal pathogens in vitro.

Two furin inhibitors, MI-1851 and MI-2415 were evaluated for their protective effects in epithelial cell models (IPEC-J2 and MDCK cells). Cultures were exposed to Shigella flexneri, EHEC or EPEC for either 2 h or 6 h. Cell viability was assessed using the CCK-8 assay. Inflammatory responses were quantified by measuring IL-6 and IL-8 levels using ELISA technique and oxidative stress in IPEC-J2 cells was monitored via extracellular hydrogen peroxide production based on Amplex red method.

Infections with EHEC, EPEC and Shigella flexneri for 6 h led to marked epithelial cell death. Treatment with either MI-1851 or MI-2415 significantly improved survival and resulted in moderated proinflammatory cytokine release (IL-6 and IL-8) in EHEC- and Shigella flexneri-infected cultures, but showed no effect against EPEC. Both inhibitors also reduced oxidative stress, with the clearest benefit observed during Shigella flexneri infection.

Furin inhibition can reduce toxin-driven cell damage and inflammation in the selected in vitro enterobacterial infections. Our findings highlight the potential of furin inhibitors as candidate as potential therapeutic agents in the future. Targeting host proteases such as furin offers a promising route to reduce reliance on antibiotics, limit resistance development and enhance treatment strategies for severe gastrointestinal pathogens.