Structural basis for the evolution of vancomycin resistance D,D-peptidases
Bibliographic record
Abstract
Emergence of high-level resistance to the last resort glycopeptide antibiotic vancomycin in Enterococcus spp. and its spread to methicillin-resistant Staphylococcus aureus is a public health threat. Resistance to vancomycin is due to substitution of the D-Ala-D-Ala terminus of cell wall precursors, which forms the antibiotic target, by D-Ala-D-Lac or D-Ala-D-Ser of low binding affinities. Resistance also requires depletion of the normal precursors catalyzed by the zinc-dependent D,D-peptidases VanX and VanY acting on dipeptide (D-Ala-D-Ala) or pentapeptide (UDP-MurNac-L-Ala-D-γ-Glu-L-Lys-D-Ala-D-Ala), respectively. Some resistance operons encode VanXY D,D-peptidase acting on both substrates. Van D,D-peptidases represent attractive targets for combinational antimicrobial therapies to curb resistance; however, the molecular basis of their specificity remains poorly understood, hindering development of potent inhibitors. Therefore we undertook detailed structure-function analysis of VanXY and VanY enzymes. Obtained structural information revealed the substrate-binding site of VanXYC as an extended cavity suitable for binding of di- or pentapeptides, contrasting with previous results showing that VanX contains a small, shallow active site. Biochemical and mutagenesis analysis identified a mobile cap over the catalytic site of VanXYC as the key structural element involved in a switch between di- and pentapeptide hydrolysis. The structures also provided the molecular basis for selectivity towards Van-susceptible peptidoglycan precursors. Overall, this study illustrates the adaptability of the D,D-peptidase fold in response to antibiotic pressure via evolution of particular structural elements that modulate substrate specificity. The results open new opportunities for structure-guided development of Van D,D-peptidases specific inhibitors as glycopeptides adjuvants. This project has been funded by NIAID under Contracts No. HHSN272200700058C and HHSN272201200026C.
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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 | 0.001 | 0.001 |
| 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 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".