A study published in Nature Microbiology describes a structure-guided strategy to inhibit Clostridioides difficile toxin B (TcdB), the primary virulence factor responsible for infectious diarrhea and colitis, leading to the development of a synthetic bile acid that protected mice from toxin-induced disease pathology.
C difficile remains the leading cause of health care–associated infectious diarrhoea, with disease severity driven largely by TcdB-mediated epithelial injury and inflammation. Although intestinal bile acids—host- and microbiota-derived metabolites, have previously been shown to inhibit TcdB activity, the molecular mechanism underlying this inhibition had not been fully defined.
Using cryogenic electron microscopy, investigators resolved high-resolution structures of TcdB bound to two inhibitory bile acids: cholic acid (methyl ester) at 2.9 Å resolution and taurochenodeoxycholic acid at 3.3 Å resolution. Structural analysis revealed that bile acids bind the toxin’s C-terminal combined repetitive oligopeptide (CROP) domain, stabilizing it in a closed conformation that allosterically masks both receptor-binding sites. This conformational locking prevents TcdB from engaging host cell receptors and entering target cells.
