Tirapazamine: an anticancer pro-drug with antimicrobial activity
Bibliographic record
Abstract
Antibiotics are one of the most successful chemotherapeutic agents in the history of mankind. They have proven their necessity from "from cradle to grave" and played a central role in global socioeconomic development for past seven decades. However, rapidly increasing bacterial resistance to existing therapy has caused an urgent need for development of new antibiotics. Tirapazamine (TPZ, 3-amino-1,2,4-benzotirazine 1,4 dioxide) is a pro-drug under phase III clinical trials for various types of cancers with unique mechanism of action. In the absence of oxygen, TPZ forms a toxic radical species with the help of cellular enzymes which ultimately causes DNA damage. Since TPZ has been successfully tested both in animal cells and yeast, we were curious to learn about its antibiotic potential. Our results indicate that fluoroquinolone resistant E. coli, Methicillin-resistant Staphylococcus aureus and C. difficile strains are sensitive to TPZ at three orders of magnitude lower concentration than what has been used in cancer treatments. Time killing experiments in E. coli provide preliminary evidence for bactericidal nature of TPZ and its involvement in DNA damage is indicated by hypersensitivity of mutants deficient in homologous recombination. In animal cells, TPZ is activated by conversion of the pro-drug by reductases. Similarly, E. coli mutants of argC, yeiA and ydhV are resistant to TPZ suggesting putative reductases produced by these loci are involved in metabolizing TPZ into a toxic compound. Pathogenic strains of C. difficile are sensitive to TPZ starting from 7.5ng/ml which is lower than other antibiotic concentrations previously tested. While further experiments are required to decipher the detail mechanism by which TPZ operates, TPZ and its derivatives might be a promising alternative for treating pathogens that are resistant to existing antibiotics.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".