Abstract
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.
Highlights
In 2018, an estimated 861,663 people died from colorectal cancer (CRC) globally, i.e., >9% of the total cancer deaths in that year (Bray et al, 2018)
To identify molecules that bind to the active site of Bacteroides fragilis toxin (BFT), two complementary in silico drug discovery techniques were used; KRIPO and MOE
The KRIPO screen resulted in 476 small molecules that were predicted to bind to thepockets of BFT3
Summary
In 2018, an estimated 861,663 people died from CRC globally, i.e., >9% of the total cancer deaths in that year (Bray et al, 2018). The importance of microbial factors from our gut microbiome in CRC pathogenesis has emerged. An important CRC-driving bacterium identified in the mucosa of more than 80% of CRC-patients is enterotoxigenic Bacteroides fragilis (ETBF) carrying the Bacteroides fragilis toxin (BFT), known as fragilysin (Boleij et al, 2015). ETBF is often found together with E. coli carrying the oncotoxin colibactin in mucosal biofilms of Familial Adenomatous Polyposis (FAP). These two oncogenic bacteria have been shown to synergize in vivo, creating a favorable environment for CRC development (Sears and Garrett, 2014; Dejea et al, 2018). Exposure to BFT is proposed as an important microbiome-derived risk factor for CRC development in humans
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