Drug Discovery and Repurposing Inhibits a Major Gut Pathogen-Derived Oncogenic Toxin

Front Cell Infect Microbiol. 2019 Oct 25:9:364. doi: 10.3389/fcimb.2019.00364. eCollection 2019.


Objective: The human intestinal microbiome plays an important role in inflammatory bowel disease (IBD) and colorectal cancer (CRC) development. One of the first discovered bacterial mediators involves Bacteroides fragilis toxin (BFT, also named as fragilysin), a metalloprotease encoded by enterotoxigenic Bacteroides fragilis (ETBF) that causes barrier disruption and inflammation of the colon, leads to tumorigenesis in susceptible mice, and is enriched in the mucosa of IBD and CRC patients. Thus, targeted inhibition of BFT may benefit ETBF carrying patients. Design: By applying two complementary in silico drug design techniques, drug repositioning and molecular docking, we predicted potential BFT inhibitory compounds. Top candidates were tested in vitro on the CRC epithelial cell line HT29/c1 for their potential to inhibit key aspects of BFT activity, being epithelial morphology changes, E-cadherin cleavage (a marker for barrier function) and increased IL-8 secretion. Results: The primary bile acid and existing drug chenodeoxycholic acid (CDCA), currently used for treating gallstones, cerebrotendinous xanthomatosis, and constipation, was found to significantly inhibit all evaluated cell responses to BFT exposure. The inhibition of BFT resulted from a direct interaction between CDCA and BFT, as confirmed by an increase in the melting temperature of the BFT protein in the presence of CDCA. Conclusion: Together, our results show the potential of in silico drug discovery to combat harmful human and microbiome-derived proteins and more specifically suggests a potential for retargeting CDCA to inhibit the pro-oncogenic toxin BFT.

Keywords: Bacteroides fragilis enterotoxin; bacterial toxin; chenodeoxycholic acid; colorectal cancer; computational drug design and discovery; drug screening; enterotoxigenic Bacteroides fragilis (ETBF); inflammatory bowel disease (IBD).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogens / metabolism*
  • Cell Transformation, Neoplastic* / chemically induced
  • Cell Transformation, Neoplastic* / drug effects
  • Drug Discovery*
  • Drug Repositioning*
  • Endotoxins / chemistry
  • Endotoxins / pharmacology
  • Gastrointestinal Microbiome* / drug effects
  • Humans
  • Metalloendopeptidases / chemistry
  • Metalloendopeptidases / pharmacology
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Structure-Activity Relationship
  • Toxins, Biological* / adverse effects
  • Toxins, Biological* / biosynthesis


  • Carcinogens
  • Endotoxins
  • Toxins, Biological
  • Metalloendopeptidases
  • fragilysin