Effects of ZinT-Mediated Zinc Sequestration on Metallo-β-Lactamase Function in Escherichia coli
Why this work is in the frame
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Bibliographic record
Abstract
β-lactams are the most prescribed antibiotic class, but their clinical utility is threatened by the production of metallo-β-lactamase (MBL) enzymes by resistant bacteria. MBLs such as NDM-1 employ zinc ions as cofactors, allowing them to degrade β-lactams. The zinc chaperone ZinT transports zinc into the cytoplasm for intracellular functions, potentially decreasing the availability of zinc in the periplasm for MBLs. We hypothesize that when zinc is limited, ZinT could impair NDM-1 activity and make bacteria more susceptible to β-lactams. To determine whether ZinT and NDM-1 compete for periplasmic zinc, bacterial growth and NDM-1 activity were tested in zinc-poor M9 minimal media for NDM-1-producing Escherichia coli strains with different levels of zinT expression. In addition to wild-type and ΔzinT knockout strains, a recombinant zinT-containing plasmid was transformed into ΔzinT knockout cells to produce a complementation strain with increased zinT expression. Growth assays were conducted in M9 with various concentrations of the β-lactam antibiotic, meropenem. Under these conditions, the ΔzinT strain grew in significantly higher meropenem concentrations than the other strains tested. NDM-1 activity assays revealed that the ΔzinT strain hydrolyzed meropenem notably faster than wild-type cells, whereas the complementation strain showed almost no hydrolysis. This suggests that the increased ZinT production in the complementation strain effectively sequestered zinc from NDM-1. These differences in meropenem hydrolysis and bacterial growth were absent in zinc-sufficient Cation-Adjusted Mueller-Hinton Broth, providing evidence that ZinT and NDM-1 compete for periplasmic zinc under nutrient deficiency. Overall, our results elucidate the effects of competing zinc requirements under zinc-deficient conditions resembling the host environment during a bacterial infection. In these zinc-deficient environments, ZinT can deprive NDM-1 of zinc, causing impaired enzymatic activity and bacterial survival. By better understanding how MBLs function under physiological conditions, future investigations can more reliably explore countermeasures to the growing threat of antibiotic resistance.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 it