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Considering the highly competitive nature of the mammalian gastrointestinal (GI) tract, these pathogens must rely on specific metabolic adaptations to establish successful infections. We hypothesized that A\/E pathogens exploit host-derived nutrients within GI mucus, including N-acetylglucosamine (GlcNAc) and N-acetylneuraminic acid (NeuNAc), to fuel their pathogenesis. To address this hypothesis, we disrupted both GlcNAc and NeuNAc metabolic pathways in\n                      <jats:italic toggle=\"yes\">Citrobacter rodentium,<\/jats:italic>\n                      a murine-specific A\/E pathogen, by deleting\n                      <jats:italic toggle=\"yes\">nagA<\/jats:italic>\n                      , which encodes the GlcNAc-6-phosphate (GlcNAc-6P) deacetylase that converts GlcNAc-6P into glucosamine-6-phosphate (GlcN-6P). Compared to wild-type (WT)\n                      <jats:italic toggle=\"yes\">C. rodentium<\/jats:italic>\n                      , the \u0394\n                      <jats:italic toggle=\"yes\">nagA<\/jats:italic>\n                      mutant showed severely attenuated colonization and pathogenesis in C57BL\/6J mice. Although \u0394\n                      <jats:italic toggle=\"yes\">nagA<\/jats:italic>\n                      cannot catabolize GlcNAc and NeuNAc, its\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      defect could not be explained by nutrient deprivation alone. Instead, \u0394\n                      <jats:italic toggle=\"yes\">nagA<\/jats:italic>\n                      exhibited higher levels of cytosolic GlcNAc-6P, slower growth rate when cultured\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , altered regulation of GlcN-6P synthesis, and increased susceptibility to cell wall-targeting stressors. Supplementation with glucosamine (GlcN, which can be directly converted into GlcN-6P) partially restored the growth and resistance to cell wall stress of \u0394\n                      <jats:italic toggle=\"yes\">nagA<\/jats:italic>\n                      without reducing GlcNAc-6P accumulation, indicating that dysregulated GlcN-6P synthesis rather than GlcNAc-6P toxicity underlies its phenotype. Together, these data reveal a previously unrecognized metabolic vulnerability in\n                      <jats:italic toggle=\"yes\">C. rodentium<\/jats:italic>\n                      where the disruption of the GlcNAc and NeuNAc metabolic pathways, by inactivating NagA, creates a sugar-phosphate imbalance that compromises cell wall integrity and pathogen fitness. Hence, targeting sugar-phosphate stress responses may provide a new therapeutic strategy against GI bacterial pathogens.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00545-25","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T13:01:46Z","timestamp":1773666106000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["The growth and pathogenesis of\n                    <i>Citrobacter rodentium<\/i>\n                    are compromised when multiple mucin sugar utilization pathways are disrupted, leading to accumulation of N-acetylglucosamine 6-phosphate"],"prefix":"10.1128","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9299-1960","authenticated-orcid":false,"given":"Zhiquan 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