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TitleStructure-guided design of a synthetic bile acid that inhibits Clostridioides difficile TcdB toxin.
Journal, issue, pagesNat Microbiol, Vol. 10, Issue 12, Page 3215-3228, Year 2025
Publish dateNov 18, 2025
AuthorsSean Miletic / Simoun Icho / Zhijie Li / John Tam / Elizabeth C Rose / Cypress E Perkins / Ali Nakhi / Xinglin Yang / Howard C Hang / John L Rubinstein / Peter I Dosa / Casey M Theriot / Roman A Melnyk /
PubMed AbstractIntestinal bile acids are a family of host and microbiota metabolites that can directly inhibit toxin B (TcdB), the primary virulence factor of Clostridioides difficile that causes infectious ...Intestinal bile acids are a family of host and microbiota metabolites that can directly inhibit toxin B (TcdB), the primary virulence factor of Clostridioides difficile that causes infectious diarrhoea and colitis. However, the mechanism underlying the inhibition is unclear. Here we used cryogenic electron microscopy and determined the structure of TcdB bound to inhibitory bile acids cholic acid (methyl ester) and taurochenodeoxycholic acid at 2.9 Å and 3.3 Å resolution, respectively. These structures revealed that bile acids lock the C-terminal CROP domain of TcdB in a conformation that allosterically masks the two receptor-binding sites and prevents target cell recognition. Guided by the structure, we synthesized gut-restricted bile acid derivatives, designed to evade the bile acid reuptake transporters within the gut. One of the derivatives, sBA-2, was retained within the gut upon oral dosing and protected mice from toxin-induced C. difficile disease pathology. Our study uncovers the structural basis of inhibition of TcdB by bile acids and its analogues, paving the way for the development of orally deliverable therapeutics against C. difficile.
External linksNat Microbiol / PubMed:41254394
MethodsEM (single particle)
Resolution2.87 - 3.59 Å
Structure data

70486

9ohc

EMDB-70486, PDB-9ohc:
CryoEM structure of Toxin B (TcdB) from clostridioides difficile complexed with taurochenodeoxycholic acid (TCDCA)
Method: EM (single particle) / Resolution: 3.28 Å

70487

9ohd

EMDB-70487, PDB-9ohd:
CryoEM structure of Toxin B (TcdB) from clostridioides difficile complexed with methyl cholate
Method: EM (single particle) / Resolution: 2.87 Å

70488

9ohe

EMDB-70488, PDB-9ohe:
CryoEM structure of apo Toxin B (TcdB) from Clostridioides difficile in the closed CROP state
Method: EM (single particle) / Resolution: 3.59 Å

70489

9ohf

EMDB-70489, PDB-9ohf:
CryoEM structure of apo Toxin B (TcdB) from Clostridioides difficile in the open CROP state
Method: EM (single particle) / Resolution: 3.19 Å

Chemicals

ChemComp-TUD:
TAUROCHENODEOXYCHOLIC ACID

PDB-1cba:
Unknown entry

Source
  • clostridioides difficile (bacteria)
KeywordsTOXIN / clostridioides difficile / Toxin B / TcdB / Bile acid / TCDCA / methyl cholate

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