Small molecule inhibitor targets OmpV to treat pandemic Vibrio cholerae infection.

Abstract

Cholera, a severe diarrhoeal illness caused by Vibrio cholerae (V. cholerae), poses a significant threat to public health worldwide. The emergence of multidrug-resistant V. cholerae strains underscores the urgent need for preventive and therapeutic interventions. In this study, we elucidate the role of outer membrane protein V (OmpV) in the virulence of V. cholerae and propose a therapeutic strategy targeting OmpV. Subcellular localization analysis shows that OmpV is present in both the bacterial outer membrane (OM) and bacterial extracellular vesicles (BEVs). When V. cholerae enters the small intestine, OmpV is activated by the CarSR two-component system in response to cationic antimicrobial peptides (CAMPs) in the small intestine, leading to increased bacterial pathogenicity. The upregulation of ompV not only augments bacterial adhesion but also promotes the internalization of BEVs into host cells, thereby increasing the delivery of cholera toxin (CT) to host cells. Computational aided drug design (CADD) shows that the small-molecule inhibitor C607-0736 is capable of disrupting the virulence functions of OmpV. Animal experiments show that C607-0736 efficiently inhibits the colonization and pathogenicity of the V. cholerae O1 and O139 strains. These findings underscore the therapeutic potential of OmpV-targeting strategies and offer promising avenues for addressing multidrug-resistant V. cholerae.