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bioRxiv · 10.1101/2025.09.08.674952

Peptide-based ligand antagonists block a Vibrio cholerae adhesin

Wang, M.·Du, G.·Yongo-Luwawa, C.·Lu, A.·Kinrade, B.·Munro, K.·Klose, K. E.·Lubell, W. D.·Davies, P. L.·Guo, S.
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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. A structure-guided approach has now 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.

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Wang, M., Du, G., Yongo-Luwawa, C., Lu, A., Kinrade, B., Munro, K., Klose, K. E., Lubell, W. D., Davies, P. L., Guo, S.. 2025-09-08. Peptide-based ligand antagonists block a Vibrio cholerae adhesin. https://doi.org/10.1101/2025.09.08.674952

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