Year: 2026
Type: preprint
Abstract: ABSTRACT Cholera is a diarrheal disease resulting from colonization of the small intestine by the Gram-negative bacterium Vibrio cholerae . The peptide-binding domain (PBD) of the adhesion protein FrhA is critical for V. cholerae intestinal colonization and biofilm formation. Antagonists of the FrhA-PBD were designed based on the tripeptide motif H-Trp-Thr-Asp-OH. Constraining the N-terminal tryptophan as a 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (Tcc) residue and X-ray analysis of a co-crystal with the FrhA-PBD define the minimal inhibitory motif. Moreover, H-(R)-Tcc-Thr-Asp-OH exhibited nanomolar binding affinity (Kd = 101 ± 30.2 nM) to the FrhA-PBD, blocking adhesion protein-mediated bacterial hemagglutination and reducing biofilm formation in vitro . Intestinal epithelial cell adhesion to the FrhA-PBD was also blocked by the Tcc tripeptide (IC□□ = 24 µM; 95% CI, 11–51 µM), which resisted chymotrypsin proteolysis. The activity of this peptidomimetic inhibitor and the atomic-level understanding of FrhA-PBD binding provide insights for developing anti-adhesion therapies to treat cholera.
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Canadian Light Source, McGill University, Centre in Green Chemistry and Catalysis, Biodiversa+, Queen's University, Université de Montréal, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Fonds de recherche du Québec – Nature et technologies
OpenAlex ID: W7212259003