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Lookup NU author(s): Dr David BolamORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2025 the Author(s).Excessive degradation of the colonic mucin layer by Bacteroides within the human gut microbiota drives inflammatory bowel disease (IBD) in mice. Bacterial carbohydrate sulfatases are key enzymes in gut colonization, and they are elevated in human IBD and correlate with disease severity. Selective inhibitors of carbohydrate sulfatases could function as sulfatase-selective drugs, allowing precise control of sulfatase activity while preserving these otherwise beneficial bacteria. Arylsulfamates are covalent inhibitors that target a catalytic formylglycine residue of steroid sulfatases, a residue that is also conserved in carbohydrate sulfatases. Here, we find that a library of aryl- and carbohydrate sulfamates is ineffective against carbohydrate sulfatases, yet can inhibit human gut microbiota (HGM) species grown on sulfated glycans. Leveraging thermal proteome profiling (TPP), we identify a lipid kinase as the target responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and reveals the adverse effects that arylsulfamates have on Bacteroides species of the HGM.
Author(s): Crawford CJ, Tomlinson CWE, Gunawan C, Chen Z, Byrne DP, Darby C, Conti MLG, Larson T, Luis AS, Elli S, Yates EA, Bolam DN, Van Der Post S, Williams SJ, Cartmell A
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences of the United States of America
Year: 2025
Volume: 122
Issue: 28
Print publication date: 15/07/2025
Online publication date: 10/07/2025
Acceptance date: 13/06/2025
Date deposited: 29/07/2025
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://doi.org/10.1073/pnas.2414331122
DOI: 10.1073/pnas.2414331122
Data Access Statement: Mass spectrometry data have been deposited in ProteomeXchange consortium via PRIDE (PXD065411) (42). Raw data files and data tables in .csv format including descriptions of samples and their associated files, and lipid annotations for all detected lipids and associated features areas across files, have been uploaded to MassIVE dataset MSV000098236 (43). All study data are included in the article and/or supporting information.
PubMed id: 40638084
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