Receptor binding mechanisms of Clostridioides difficile toxin B and implications for therapeutics development

Clostridioides difficile is classified as an urgent antibiotic resistance threat by the Centers for Disease Control and Prevention (CDC). C. difficile infection (CDI) is mainly caused by the C. difficile exotoxin TcdB, which invades host cells via receptor-mediated endocytosis. However, many natural variants of TcdB have been identified including some from the hypervirulent strains, which pose significant challenges for developing effective CDI therapies. Here, we review the recent research progress on the molecular mechanisms by which TcdB recognizes Frizzed proteins (FZDs) and chondroitin sulfate proteoglycan 4 (CSPG4) as two major host receptors. We suggest that the receptor-binding sites and several previously identified neutralizing epitopes on TcdB are ideal targets for the development of broad-spectrum inhibitors to protect against diverse TcdB variants.

Automated summary

This article reviews recent research progress on the molecular mechanisms by which the Clostridioides difficile exotoxin TcdB recognizes Frizzed proteins (FZDs) and chondroitin sulfate proteoglycan 4 (CSPG4) as two major host receptors. The authors suggest that the receptor-binding sites and neutralizing epitopes on TcdB are ideal targets for the development of broad-spectrum inhibitors against various TcdB variants.