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Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity.
- Source :
-
Communications biology [Commun Biol] 2021 Mar 04; Vol. 4 (1), pp. 280. Date of Electronic Publication: 2021 Mar 04. - Publication Year :
- 2021
-
Abstract
- Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of β-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial β-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (K <subscript>i</subscript> = 0.0045 and 105 μM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells.
- Subjects :
- Animals
Bacteria enzymology
Cell Line
Diarrhea chemically induced
Diarrhea microbiology
Disease Models, Animal
Female
Glucuronidase metabolism
Humans
Mice, Inbred BALB C
Mice
Bacteria drug effects
Colon microbiology
Diarrhea prevention & control
Enzyme Inhibitors pharmacology
Gastrointestinal Microbiome drug effects
Glucuronidase antagonists & inhibitors
Imino Pyranoses pharmacology
Irinotecan
Uronic Acids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2399-3642
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Communications biology
- Publication Type :
- Academic Journal
- Accession number :
- 33664385
- Full Text :
- https://doi.org/10.1038/s42003-021-01815-w