Arylsulfamates inhibit colonic Bacteroidota growth through a sulfatase- independent mechanism
成果类型：
Article
署名作者：
Crawford, Conor J.; Tomlinson, Charles W. E.; Gunawan, Christian; Chen, Zongjia; Byrne, Dominic P.; Darby, Cosette; Conti, Martina L. G.; Larson, Tony; Luis, Ana S.; Elli, Stefano; Yates, Edwin A.; Bolam, David N.; van der Post, Sjoerd; Williams, Spencer J.; Cartmell, Alan
署名单位：
Max Planck Society; University of York - UK; University of York - UK; University of York - UK; University of Melbourne; University of Melbourne; University of Liverpool; Newcastle University - UK; University of Gothenburg; SciLifeLab; University of Gothenburg
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-12888
DOI：
10.1073/pnas.2414331122
发表日期：
2025-07-15
关键词：
muc2 mucin
microbiota
irosustat
colitis
analogs
cancer
ACID
摘要：
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.