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

Paul Metz, Martijn J.H. Tjan, Shaoguang Wu, Mehrosh Pervaiz, Susanne Hermans, Aishwarya Shettigar, Cynthia L. Sears, Tina Ritschel, Bas E. Dutilh, Annemarie Boleij

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number364
JournalFrontiers in Cellular and Infection Microbiology
Volume9
DOIs
StatePublished - Oct 25 2019

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Drug Repositioning
Chenodeoxycholic Acid
Drug Discovery
Colorectal Neoplasms
Bacteroides fragilis
Microbiota
Inflammatory Bowel Diseases
Computer Simulation
Cerebrotendinous Xanthomatosis
Drug Design
Metalloproteases
Gallstones
Cadherins
Constipation
Bile Acids and Salts
Interleukin-8
Freezing
Colon
Carcinogenesis
Mucous Membrane

Keywords

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

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Drug Discovery and Repurposing Inhibits a Major Gut Pathogen-Derived Oncogenic Toxin. / Metz, Paul; Tjan, Martijn J.H.; Wu, Shaoguang; Pervaiz, Mehrosh; Hermans, Susanne; Shettigar, Aishwarya; Sears, Cynthia L.; Ritschel, Tina; Dutilh, Bas E.; Boleij, Annemarie.

In: Frontiers in Cellular and Infection Microbiology, Vol. 9, 364, 25.10.2019.

Research output: Contribution to journalArticle

Metz, Paul ; Tjan, Martijn J.H. ; Wu, Shaoguang ; Pervaiz, Mehrosh ; Hermans, Susanne ; Shettigar, Aishwarya ; Sears, Cynthia L. ; Ritschel, Tina ; Dutilh, Bas E. ; Boleij, Annemarie. / Drug Discovery and Repurposing Inhibits a Major Gut Pathogen-Derived Oncogenic Toxin. In: Frontiers in Cellular and Infection Microbiology. 2019 ; Vol. 9.
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AU - Metz, Paul

AU - Tjan, Martijn J.H.

AU - Wu, Shaoguang

AU - Pervaiz, Mehrosh

AU - Hermans, Susanne

AU - Shettigar, Aishwarya

AU - Sears, Cynthia L.

AU - Ritschel, Tina

AU - Dutilh, Bas E.

AU - Boleij, Annemarie

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N2 - 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.

AB - 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.

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KW - colorectal cancer

KW - computational drug design and discovery

KW - drug screening

KW - enterotoxigenic Bacteroides fragilis (ETBF)

KW - inflammatory bowel disease (IBD)

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