The growth and pathogenesis of <i>Citrobacter rodentium</i> is compromised by disrupted mucin sugar pathways that accumulate N-acetylglucosamine 6-phosphate
Bibliographic record
Abstract
Abstract Many enteric bacterial pathogens, including the attaching/effacing (A/E) Escherichia coli strains, cause acute gastroenteritis in humans. 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 the monosaccharides N-acetylglucosamine (GlcNAc) and N-acetylneuraminic acid (NeuNAc) to fuel their pathogenesis. Using Citrobacter rodentium, a murine-specific A/E pathogen, we disrupted both GlcNAc and NeuNAc catabolism by deleting nagA , which encodes the GlcNAc-6-phosphate (GlcNAc-6P) deacetylase that converts GlcNAc-6P into glucosamine-6-phosphate (GlcN-6P). The Δ nagA mutant displayed dramatically impaired colonization in C57BL/6J mice and accumulated significant levels of GlcNAc-6P, unlike the Δ mana strain, a mutant lacking all GlcNAc and NeuNAc transporters, suggesting that the attenuation was due to sugar-phosphate stress rather than nutrient deprivation alone. Supplementation with glucosamine (GlcN) restored growth, indicating that dysregulated GlcN-6P synthesis, rather than GlcNAc-6P toxicity, underlies the defect. Furthermore, Δ nagA exhibited increased susceptibility to several cell wall-dependent stress conditions, in concert with compromised peptidoglycan biosynthesis due to reduced UDP-GlcNAc synthesis. These findings reveal a previously unrecognized metabolic vulnerability in C. rodentium and suggest that targeting sugar-phosphate stress responses may provide a new therapeutic strategy against GI bacterial pathogens. Importance Enteric pathogens like Citrobacter rodentium can exploit sugars, including N-acetylglucosamine and N-acetylneuraminic acid, derived from intestinal mucus to grow and infect their hosts. This study shows that disruption of mucin-derived sugar catabolism impairs the fitness of C. rodentium in infecting the murine intestine by causing the accumulation of a toxic intermediate of mucin sugar metabolism. Rather than impaired nutrient acquisition, the bacteria are impaired due to the buildup of N-acetylglucosamine-6-phosphate, which depletes substrates for peptidoglycan synthesis. This metabolic bottleneck weakens the bacterial cell wall, making the pathogen more sensitive to environmental stress. These findings identify a conserved metabolic stress response that could be targeted to combat enteric pathogen infections.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".