TY - JOUR
T1 - Drug Discovery and Repurposing Inhibits a Major Gut Pathogen-Derived Oncogenic Toxin
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
N1 - Funding Information:
We would like to thank researchers at the CMBI, Radboudumc (Aya Hefnawy, Gert Vriend, Fabio Baroni, and Joanna Lange), the Sears Laboratory at Johns Hopkins Medical Institutions (Christine Craig, Julia Drewes, Pauline Myles, Payam Fathi, and Xinqun Wu), and the Department of Pathology, Radboudumc (Blanca Scheijen and professor I. D. Nagtegaal) for their continued help and enthusiasm. Funding. This project was financially supported by the Radboud Honours Programme Medical Sciences and Johns Hopkins resources NIH R01CA179440 (CS, PI) and Bloomberg Philanthropies. PM received a student internship grant from the Koningin Wilhelmina Fonds (KWF) voor de Nederlandse Kankerbestrijding (Dutch Cancer Society). MT received a grant from Radboud University. CS was supported, in part, by a grant from Bristol Myer Squibb. BD was supported by Netherlands Organization for Scientific Research (NWO) Vidi grant 864.14.004. AB was supported by NWO Veni grant 016.166.089. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© Copyright © 2019 Metz, Tjan, Wu, Pervaiz, Hermans, Shettigar, Sears, Ritschel, Dutilh and Boleij.
PY - 2019/10/25
Y1 - 2019/10/25
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.
KW - Bacteroides fragilis enterotoxin
KW - bacterial toxin
KW - chenodeoxycholic acid
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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U2 - 10.3389/fcimb.2019.00364
DO - 10.3389/fcimb.2019.00364
M3 - Article
C2 - 31709196
AN - SCOPUS:85074741857
SN - 2235-2988
VL - 9
JO - Frontiers in Cellular and Infection Microbiology
JF - Frontiers in Cellular and Infection Microbiology
M1 - 364
ER -