The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile

Int J Mol Sci. 2021 Mar 13;22(6):2926. doi: 10.3390/ijms22062926.


Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.

Keywords: CDT; CDTa; CDTb; Clostridioides difficile; binary toxin; infectious disease; protein structural biology.

Publication types

  • Review

MeSH terms

  • ADP-Ribosylation / drug effects
  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism
  • Actin Cytoskeleton / ultrastructure
  • Actins / deficiency
  • Actins / genetics
  • Anti-Bacterial Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / antagonists & inhibitors*
  • Bacterial Toxins / chemistry
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism
  • Binding Sites
  • Clostridioides difficile / drug effects
  • Clostridioides difficile / genetics
  • Clostridioides difficile / metabolism
  • Clostridioides difficile / pathogenicity*
  • Cross Infection / drug therapy*
  • Cross Infection / metabolism
  • Cross Infection / microbiology
  • Cross Infection / pathology
  • Endocytosis / drug effects
  • Enterocolitis, Pseudomembranous / drug therapy*
  • Enterocolitis, Pseudomembranous / metabolism
  • Enterocolitis, Pseudomembranous / microbiology
  • Enterocolitis, Pseudomembranous / pathology
  • Enterotoxins / antagonists & inhibitors*
  • Enterotoxins / chemistry
  • Enterotoxins / genetics
  • Enterotoxins / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Epithelial Cells / ultrastructure
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Domains
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary


  • Actins
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Bacterial Toxins
  • Enterotoxins
  • tcdA protein, Clostridium difficile
  • toxB protein, Clostridium difficile