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

Area of Science:

• Microbiology
• Gastroenterology
• Drug Discovery

Background:

• The human intestinal microbiome influences inflammatory bowel disease (IBD) and colorectal cancer (CRC).
• Bacteroides fragilis toxin (BFT) from enterotoxigenic B. fragilis (ETBF) disrupts the colon barrier, promotes inflammation, and is linked to IBD and CRC.
• Targeting BFT may offer therapeutic benefits for ETBF-colonized patients.

Purpose of the Study:

• To identify potential inhibitors of BFT using in silico drug design.
• To evaluate the efficacy of identified compounds against BFT's effects on colon epithelial cells.

Main Methods:

• Employed drug repositioning and molecular docking to predict BFT inhibitors.
• Tested top candidates in vitro on HT29/c1 CRC cells to assess inhibition of BFT-induced morphology changes, E-cadherin cleavage, and IL-8 secretion.

Main Results:

• Chenodeoxycholic acid (CDCA), a primary bile acid and existing drug, significantly inhibited all tested cellular responses to BFT.
• CDCA directly interacted with BFT, evidenced by an increased melting temperature of the BFT protein.

Conclusions:

• In silico drug discovery can identify inhibitors for harmful microbiome-derived proteins.
• CDCA shows potential for repurposing to neutralize the pro-oncogenic BFT toxin.