Angucyclinones rescue PhLOPS <sub>A</sub> antibiotic activity by inhibiting Cfr-dependent antibiotic resistance
Bibliographic record
Abstract
ABSTRACT Methylation of the ribosome is a prevalent strategy conferring resistance to antibiotics that inhibit protein synthesis. Methylation is catalyzed by several distinct enzymes, many encoded on mobile genetic elements widespread in bacteria. One enzyme that is increasingly common in Gram-positive pathogens is Cfr. This radical S-adenosyl-L-methionine rRNA methylase confers resistance to the antibiotics ph enicols, l incosamides, o xazolidinones, p leuromutilins, and s treptogramin A (PhLOPS A ) via methylation of A2503 of the 23S rRNA of the large ribosomal subunit. One strategy to safeguard the utility of these antibiotics is to identify inhibitors of Cfr-dependent methylation that may rescue antibiotic activity. We screened our in-house library of microbial natural product extracts against Cfr + Escherichia coli and identified an extract from Streptomyces WAC01849 that potentiated the PhLOPS A antibiotic linezolid in a Cfr-dependent manner. We isolated the active angucyclinones 8- O -methyltetrangomycin (MTN) and 8- O -methyltetrangulol (MTL) from this extract. Both compounds selectively potentiated representatives of the PhLOPS A antibiotics in Escherichia coli and methicillin-resistant Staphylococcus aureus in a Cfr-dependent manner. Finally, we observed inhibition of Cfr-mediated ribosome methylation in cells treated with MTN and MTL. Our findings suggest that MTN and MTL interfere with Cfr-dependent methylation to protect the efficacy of the PhLOPS A antibiotics and offer a unique chemical scaffold that may be applied in developing clinically useful Cfr inhibitors. IMPORTANCE Cfr is an antibiotic resistance enzyme that inhibits five clinically important antibiotic classes, is genetically mobile, and has a minimal fitness cost, making Cfr a serious threat to antibiotic efficacy. The significance of our work is in discovering molecules that inhibit Cfr-dependent methylation of the ribosome, thus protecting the efficacy of the PhLOPS A antibiotics. These molecules are the first reported inhibitors of Cfr-mediated ribosome methylation and, as such, will guide the further discovery of chemical scaffolds against Cfr-mediated antibiotic resistance. Our work acts as a foundation for further development of molecules that safeguard the PhLOPS A antibiotics from Cfr.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".