GW779439X and Its Pyrazolopyridazine Derivatives Inhibit the Serine/Threonine Kinase Stk1 and Act As Antibiotic Adjuvants against β-Lactam-Resistant <i>Staphylococcus aureus</i>
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Bibliographic record
Abstract
As antibiotic resistance rises, there is a need for strategies such as antibiotic adjuvants to conserve already-established antibiotics. A family of bacterial kinases known as the penicillin-binding-protein and serine/threonine kinase-associated (PASTA) kinases has attracted attention as targets for antibiotic adjuvants for β-lactams. Here, we report that the pyrazolopyridazine GW779439X sensitizes methicillin-resistant Staphylococcus aureus (MRSA) to various β-lactams through inhibition of the PASTA kinase Stk1. GW779439X potentiates β-lactam activity against multiple MRSA and MSSA isolates, including the sensitization of a ceftaroline-resistant isolate to ceftaroline. In silico modeling was used to guide the synthesis of GW779439X derivatives. The presence and orientation of GW779439X's methylpiperazine moiety was crucial for robust biochemical and microbiologic activity. Taken together, our data provide a proof of concept for developing the pyrazolopyridazines as selective Stk1 inhibitors which act across S. aureus isolates.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| 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 it