Exploring DNA Topoisomerases as Targets of Novel Therapeutic Agents in the Treatment of Infectious Diseases
Bibliographic record
Abstract
DNA topoisomerases are ubiquitous enzymes needed to overcome topological problems encountered during DNA replication, transcription, recombination and maintenance of genomic stability. They have proved to be valuable targets for therapy, in part because some anti-topoisomerase agents act as poisons. Bacterial DNA gyrase and topoisomerase IV (type IIA topoisomerases) are targets of fluoroquinolones while human topoisomerase I (a type IB topoisomerase) and topoisomerase II are targets of various anticancer drugs. Bacterial type IA topoisomerase share little sequence homology to type IB or type IIA topoisomerases, but all topoisomerases have the potential of having the covalent phosphotyrosine DNA cleavage intermediate trapped by drug action. Recent studies have demonstrated that stabilization of the covalent complex formed by bacterial topoisomerase I and cleaved DNA can lead to bacterial cell death, supporting bacterial topoisomerase I as a promising target for the development of novel antibiotics. For current antibacterial therapy, the prevalence of fluoroquinolone-resistant bacterial pathogens has become a major public health concern, and efforts are directed towards identifying novel inhibitors of bacterial type IIA topoisomerases that are not affected by fluoroquinolone resistant mutations on the gyrase or topoisomerase IV genes. For anti-viral therapy, poxviruses encode their own type IB topoisomerases; these enzymes differ in drug sensitivity from human topoisomerase I. To confront potential threat of small pox as a weapon in terrorist attacks, vaccinia virus topoisomerase I has been targeted for discovery of anti-viral agents. These new developments of DNA topoisomerases as targets of novel therapeutic agents being reviewed here represent excellent opportunities for drug discovery in the treatment of infectious 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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".