A peptidomimetic inhibitor blocks Vibrio cholerae adhesin FrhA.
Wang, M.; Yongo-Luwawa, C.; Zhang, L.; Williston, R.; Presley, J. F.; Mehboodi, Z.; Reinhardt, D.; Klose, K. E.; Lubell, W. D.; Guo, S.
Show abstract
Cholera is a diarrheal disease from colonization of the small intestine by the Gram-negative bacterium Vibrio cholerae. Cholera remains a critical public health concern due to limitations in therapy and rising antibiotic resistance. The peptide-binding domain (PBD) of the adhesion protein FrhA is critical for V. cholerae intestinal colonization and biofilm formation. In a program targeted on blocking cholera infection, antagonists of the FrhA-PBD are described based on a tripeptide motif. Notably, constraint of the N-terminal tryptophan residue using 1,2,3,4-tetrahydro-{beta}-carboline-3-carboxylic acid (Tcc) and co-crystallization of H-(S)-Tcc-Thr-Asp-OH with an FrhA construct has provided structural information to guide inhibitor design. The diastereomer (R)-Tcc-Thr-Asp exhibited nanomolar binding affinity (Kd = 101 {+/-} 30.2 nM). H-(R)-Tcc-Thr-Asp-OH blocked bacterial hemagglutination mediated by FrhA-PBD and reduced biofilm formation in vitro. Moreover, it showed greater resistance to the digestive enzyme chymotrypsin than previously reported inhibitory pentapeptides, offering potential proteolytic stability while blocking FrhA-PBD-mediated adhesion in the intestine.
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