# Peptide‐based ligand antagonists block a Vibrio cholerae adhesin

## TL;DR

Researchers designed peptides that block Vibrio cholerae adhesion, offering a new way to treat cholera without promoting drug resistance.

## Contribution

A structure-guided design of D-amino acid-containing tripeptides with nanomolar affinity for blocking Vibrio cholerae adhesion.

## Key findings

- X-ray crystallography revealed how AGYTD binds tightly to the FrhA-PBD Ca2+ pocket.
- D-amino acid-containing tripeptides showed higher affinity and metabolic stability compared to AGYTD.
- The findings provide a structural blueprint for anti-adhesion therapeutics against cholera.

## Abstract

Vibrio cholerae, the causative agent of cholera, uses surface proteins such as the repeats‐in‐toxin (RTX) adhesin FrhA to colonize hosts and initiate infection. Blocking bacterial adhesion represents a promising therapeutic strategy to treat infections without promoting drug resistance. FrhA contains a peptide‐binding domain (PBD) that is key for hemagglutination, human epithelial cell binding, and V. cholerae biofilm formation. Previous studies identified a lead pentapeptide ligand with the sequence Ala‐Gly‐Tyr‐Thr‐Asp (AGYTD) that blocks V. cholerae colonization of the mouse small intestine at high micromolar concentrations. In this study, a structure‐guided approach identified a minimal D‐amino acid‐containing tripeptide motif with higher affinity for the FrhA‐PBD and predicted metabolic stability. Our results contribute to the development of anti‐adhesion strategies to combat infections.

Impact statementOur study elucidates the molecular basis of peptide recognition by the Vibrio cholerae adhesin FrhA and develops minimal D‐amino‐acid peptides that block adhesion with nanomolar affinity. These findings advance understanding of RTX adhesins and provide a structural blueprint for next‐generation anti‐adhesion therapeutics against cholera and related infections.

Our study elucidates the molecular basis of peptide recognition by the Vibrio cholerae adhesin FrhA and develops minimal D‐amino‐acid peptides that block adhesion with nanomolar affinity. These findings advance understanding of RTX adhesins and provide a structural blueprint for next‐generation anti‐adhesion therapeutics against cholera and related infections.

The structure of a peptide‐binding domain of the Vibrio cholerae adhesin FrhA was solved by X‐ray crystallography, revealing how the inhibitory peptide AGYTD binds tightly at its Ca2+‐coordinated pocket. Structure‐guided design incorporating D‐amino acids enhanced binding affinity, providing a foundation for developing anti‐adhesion therapeutics against cholera.