Identification of Biosynthetic Inhibitors of Virulence Factor Entry Into Mammalian Cells
Bibliographic record
Abstract
Clostridioides difficile toxin B (TcdB) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the primary virulence factors behind the C. difficile infection (CDI) and the coronavirus disease 2019 (COVID-19) pandemic, respectively. Current treatment against CDI, using antibiotics, leads to sustained gut dysbiosis, a known risk factor for the disease, and subsequent recurrence in up to 65% of patients. Targeting TcdB, the disease causing agent behind CDI, through use of the monoclonal antibody bezlotoxumab leads to reduction of disease recurrence but the marginal efficacy due to the intravenous route of administration and high cost limits the widespread use of the drug. As such, discovery of a gut-acting TcdB inhibitor is necessary. The focus of this thesis is on developing said inhibitors. Using an in vitro, ex vivo, and in vivo approach, we identified bile acids as potent inhibitors of TcdB and developed a novel gut-restricted bile acid capable of protecting mice from recurrence of CDI. Additionally, we demonstrate that physiological levels of bile acids from mouse gastrointestinal tract protects against TcdB, providing a baseline protection against the toxin. However, in disease state, the increased levels of TcdB overcome this protection and lead to tissue damage and disease symptoms. Interestingly, protection can be restored with addition of exogenous bile acids. We also identified inhibition of endosomal acidification by targeting vacuolar ATPase (V-ATPase) to be an effective mechanism by which TcdB is protected against. This finding led us to explore the possibility of using endosomal acidification inhibitors to protect against SARS-CoV-2 since both TcdB and SARS-CoV-2 require endosomal acidification to gain access to the host cytosol. Our findings demonstrate that, much like TcdB, SARS-CoV-2 is neutralized following the inhibition of endosomal acidification via inactivation of V-ATPase activity. In summary, this thesis highlights the advantages of using host-derived compounds such as bile acids or targeting host-dependent mechanism such as endosomal acidification to inhibit primary virulence factors and protect against their respective diseases.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".