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TitleDe novo design of potent inhibitors of clostridial family toxins.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 39, Page e2509329122, Year 2025
Publish dateSep 30, 2025
AuthorsRobert J Ragotte / Huazhu Liang / John Tam / Sean Miletic / Jacob M Berman / Roger Palou / Connor Weidle / Zhijie Li / Matthias Glögl / Greg L Beilhartz / Kenneth D Carr / Andrew J Borst / Brian Coventry / Xinru Wang / John L Rubinstein / Mike Tyers / Daniel Schramek / Roman A Melnyk / David Baker /
PubMed Abstract remains a leading cause of hospital-acquired infections, with its primary virulence factor, toxin B (TcdB), responsible for severe colitis and recurrent disease. The closely related toxin, TcsL, ... remains a leading cause of hospital-acquired infections, with its primary virulence factor, toxin B (TcdB), responsible for severe colitis and recurrent disease. The closely related toxin, TcsL, from , causes a rarer but often fatal toxic shock syndrome, particularly in gynecological and obstetric contexts. We report the de novo design of small protein minibinders that directly neutralize TcdB and TcsL by preventing their entry into host cells. Using deep learning and Rosetta-based approaches, we generated high-affinity minibinders that protect cells from intoxication with picomolar potency and, in the case of TcsL, prolonged survival following lethal toxin challenge in mice. The designed proteins against TcdB demonstrate exceptional stability in proteolytic and acidic environments, making them well-suited for oral delivery-a valuable feature for treating infections localized to the gastrointestinal tract. For TcsL, potent inhibitors were identified from 48 initial designs and 48 optimized designs, highlighting the potential of computational design for rapidly developing countermeasures against life-threatening bacterial toxins.
External linksProc Natl Acad Sci U S A / PubMed:40982695 / PubMed Central
MethodsEM (single particle)
Resolution3.02 - 4.61 Å
Structure data

45739

9cm5

EMDB-45739, PDB-9cm5:
CryoEM Strucuture of TcdB in complex with De Novo Minibinder fzd48
Method: EM (single particle) / Resolution: 4.61 Å

48223

9mf4

EMDB-48223, PDB-9mf4:
De novo designed minibinder complexed with Clostridioides difficile Toxin B
Method: EM (single particle) / Resolution: 3.02 Å

Source
  • Escherichia coli (E. coli)
  • synthetic construct (others)
  • clostridioides difficile (bacteria)
KeywordsTOXIN / TcdB / Clostridium difficile / C. Diff. / fzd48 / De Novo Minibinder / minibinder / de novo / inhibitor

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