Munneke Matthew J, Yuan Yifeng, Preisner Eva C, Shelton Catherine D, Carroll Darian T, Kirchoff Nicole S, Dickson Ken P, Cantu Jose O, Douglass Martin V, Calcutt M Wade, Gibson-Corley Katherine N, Nicholson Maribeth R, Byndloss Mariana X, Britton Robert A, de Crécy-Lagard Valérie, Skaar Eric P
Department of Pathology, Microbiology, and Immunology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232-7917, USA.
Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA.
Cell Host Microbe. 2025 Apr 9;33(4):573-588.e7. doi: 10.1016/j.chom.2025.03.001. Epub 2025 Mar 25.
Nucleotides are essential building blocks for major cellular macromolecules and are critical for life. Consequently, bacterial pathogens must acquire or synthesize nucleotides during infection. Clostridioides difficile is the most common hospital-acquired gastrointestinal infection, and nutrient acquisition is critical for pathogenesis. However, the impact of nucleotide metabolism on C. difficile infection remains unclear. Here, we discover that 4-thiouracil (4-TU), a pyrimidine analog present in the human gut, is toxic to commensal bacteria. 4-TU hijacks the uracil salvage pathway for incorporation into RNA through the uracil phosphoribosyltransferase activity encoded by PyrR and Upp. C. difficile can salvage 4-TU as a pyrimidine source through the enzymatic action of a thiouracil desulfurase (TudS), thereby contributing to C. difficile fitness in mice fed 4-TU or MiniBioreactor models of infection containing exogenous 4-TU. Collectively, these results reveal a molecular mechanism for C. difficile to utilize a poisonous pyrimidine analog in the vertebrate gut to outcompete commensal microbes.
核苷酸是主要细胞大分子的基本组成部分，对生命至关重要。因此，细菌病原体在感染过程中必须获取或合成核苷酸。艰难梭菌是最常见的医院获得性胃肠道感染病原体，营养获取对其致病机制至关重要。然而，核苷酸代谢对艰难梭菌感染的影响仍不清楚。在此，我们发现人类肠道中存在的嘧啶类似物4-硫尿嘧啶（4-TU）对共生细菌有毒。4-TU通过PyrR和Upp编码的尿嘧啶磷酸核糖基转移酶活性劫持尿嘧啶补救途径以掺入RNA。艰难梭菌可通过硫尿嘧啶脱硫酶（TudS）的酶促作用将4-TU作为嘧啶来源进行补救，从而有助于艰难梭菌在喂食4-TU的小鼠或含有外源性4-TU的感染微型生物反应器模型中的适应性。总体而言，这些结果揭示了艰难梭菌在脊椎动物肠道中利用有毒嘧啶类似物以胜过共生微生物的分子机制。
