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
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam 14476, Germany.
Department of Biology, University of York, York YO10 5DD, United Kingdom.
Proc Natl Acad Sci U S A. 2025 Jul 15;122(28):e2414331122. doi: 10.1073/pnas.2414331122. Epub 2025 Jul 10.
Excessive degradation of the colonic mucin layer by 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 species of the HGM.
人类肠道微生物群中[具体物质]对结肠粘蛋白层的过度降解会导致小鼠患炎症性肠病（IBD）。细菌碳水化合物硫酸酯酶是肠道定植中的关键酶，在人类IBD中其水平升高且与疾病严重程度相关。碳水化合物硫酸酯酶的选择性抑制剂可作为硫酸酯酶选择性药物，在保留这些原本有益细菌的同时精确控制硫酸酯酶活性。芳基硫酸酯是靶向类固醇硫酸酯酶催化甲酰甘氨酸残基的共价抑制剂，该残基在碳水化合物硫酸酯酶中也保守。在此，我们发现一系列芳基和碳水化合物硫酸酯对碳水化合物硫酸酯酶无效，但能抑制在硫酸化聚糖上生长的人类肠道微生物群（HGM）物种。利用热蛋白质组分析（TPP），我们确定一种脂质激酶是造成这些效应的靶点。这项工作凸显了开发针对碳水化合物硫酸酯酶的特异性抑制剂的必要性，并揭示了芳基硫酸酯对HGM物种的不利影响。
