Handling Editor: Elaine R. Mardis
ABSTRACT
Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.
This article has an associated First Person interview with the joint first authors of the paper.
Footnotes
Competing interests
V.A.P.M.d.S. is a shareholder and director of GeneXplain GmbH. A.K. is a shareholder and director of LifeGlimmer GmbH.
Author contributions
Conceptualization: M.H.R.W., W.M., C.P., M.D.B.; Methodology: K.L., S.P., P.S., H.E., C.A.D., B.J.C., V.P., V.A.P.M.d.S., M.D.B.; Software: P.S.; Validation: P.S.; Formal analysis: K.L., S.P., P.S., F.B., L.M., M.K., A.K., M.D.B.; Investigation: K.L., S.P., E.S., M.K., H.E., A.K., M.D.B.; Resources: D.S., V.A.P.M.d.S., W.M., D.M.P.; Data curation: K.L., S.P., P.S., F.B., H.E., D.S., A.K., M.D.B.; Writing - original draft: P.S., L.M., H.E., A.K., M.D.B.; Writing - review & editing: K.L., S.P., E.S., D.S., C.A.D., B.J.C., V.P., V.A.P.M.d.S., W.M., D.M.P., C.P., M.D.B.; Visualization: F.B., L.M., H.E., D.S., V.A.P.M.d.S., M.D.B.; Supervision: D.S., B.J.C., V.A.P.M.d.S., W.M., D.M.P., C.P., M.D.B.; Project administration: V.A.P.M.d.S., A.K., W.M., C.P.; Funding acquisition: M.H.R.W., V.A.P.M.d.S., A.K., W.M., C.P.
Funding
This work was supported by the European Union Seventh Framework Programme (FP7/2012-2017) under the SysmedIBD grant, agreement no. 305564.
Supplementary information
Supplementary information available online at https://dmm.biologists.org/lookup/doi/10.1242/dmm.044040.supplemental
- Received December 31, 2019.
- Accepted September 8, 2020.
- © 2020. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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