Enzyme-mediated aminoglycoside resistance without target mimicry
Bibliographic record
Abstract
The primary mode of resistance to aminoglycoside antibiotics is through chemical modification catalyzed by aminoglycoside-modifying enzymes. Numerous structural studies of these enzymes have invariably shown that they bind aminoglycosides in the same lowest-energy conformation as the intended target for these antibiotics, the A site of the bacterial ribosome. Presumably, the binding mode mimicry enables these enzymes to compete successfully with the target, thus conferring effective resistance. Here we present the first structural and functional studies of two aminoglycoside-modifying enzymes that do not use target mimicry, AAC(3)-Ia and AAC(3)-XIa. X-ray diffraction studies reveal that these enzymes bind aminoglycoside antibiotics in a conformation where the central 2-deoxystreptamine ring is in boat conformation. The effect of this non-canonical binding mode on the enzymes' ability to modify antibiotics is assessed in silico and in vitro, and its impact for conferring resistance is assessed in vivo. Overall, the results show that target mimicry, while advantageous, is not an essential strategy for aminoglycoside-modifying enzymes to be effective in conferring resistance.
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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 | 0.001 | 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".