Language
English
Publication Date
4-9-2025
Journal
Cell Host & Microbe
DOI
10.1016/j.chom.2025.03.001
PMID
40139192
PMCID
PMC11985272
PubMedCentral® Posted Date
4-9-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
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.
Keywords
Clostridioides difficile, Thiouracil, Animals, Mice, Clostridium Infections, Humans, Pentosyltransferases, RNA, Bacterial, Bacterial Proteins, Gastrointestinal Tract, Clostridioides difficile, nucleotide, TudS, 4-thiouracil, PyrR, Upp, RNA, pyrimidine analog
Published Open-Access
yes
Recommended Citation
Munneke, Matthew J; Yuan, Yifeng; Preisner, Eva C; et al., "A Thiouracil Desulfurase Protects Clostridioides Difficile Rna From 4-Thiouracil Incorporation, Providing a Competitive Advantage in the Gut" (2025). Faculty, Staff and Students Publications. 8773.
https://digitalcommons.library.tmc.edu/baylor_docs/8773