Vgb from<i>Staphylococcus aureus</i>Inactivates Streptogramin B Antibiotics by an Elimination Mechanism Not Hydrolysis
Bibliographic record
Abstract
The streptogramin antibiotics were identified almost 50 years ago but have only recently found clinical use as a consequence of the increase in multidrug-resistant bacteria. Despite the fact that these antibiotics have historically not found intense clinical use, resistance to streptogramins exists. Streptogramins consist of a mixture of two components: cyclic polyunsaturated macrolactones (group A) and cyclic hexadepsipeptides (group B). The latter are cyclized through an ester bond between the hydroxyl group of an N-terminal threonine and the C-terminal carboxyl. Resistance to the B streptogramins can occur through the production of enzymes such as Vgb from Staphylococcus aureus. This enzyme had been assumed to be a lactonase that inactivates the cyclic antibiotic by linearization through hydrolytic cleavage of the ester bond. We have expressed recombinant Vgb in quantity and, using a combination of mass spectrometry, NMR, and synthesis of model depsipeptides, show unequivocally that streptogramin B inactivation does not involve hydrolysis of the ester bond. Rather, the hexadepsipeptide is linearized through an elimination reaction across the ester bond generating an N-terminal dehydrobutyrine group. Therefore, Vgb is not a hydrolase but a lyase. We also have explored the activity of Vgb orthologues present in the chromosomes of various bacteria including Bordetella pertussis and Streptomyces coelicolor and have determined that these enzymes also show streptogramin B inactivation through an elimination mechanism indistinguishable to that used by Vgb. These results demonstrate that Vgb is a member of a large group of streptogramin B lyases that are present not only in resistant clinical isolates but also in the chromosomes of many bacteria. There is therefore a significant reservoir of streptogramin resistance enzymes in the environment, which has the potential to impact the long-term utility of these antibiotics. This research establishing the molecular mechanism of streptogramin resistance therefore has the potential to be exploited in the discovery of inhibitory compounds that could rescue antibiotic activity even in the presence of resistance elements.
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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 | 0.000 | 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 | 0.000 | 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".