Targeting the MEK1/2 pathway to combat <i>Staphylococcus aureus</i> infection and inflammation in cystic fibrosis
Bibliographic record
Abstract
ABSTRACT Staphylococcus aureus infections remain an ongoing challenge for people with cystic fibrosis (PwCF), with the increased global prevalence of multidrug-resistant strains requiring new therapeutic approaches. Our previous studies demonstrated anti-inflammatory effects of several MEK1/2 inhibitor compounds, including PD0325901, CI-1040, and trametinib, in human phagocytes from PwCF and a murine S. aureus pulmonary infection model (M. De, G. Serpa, E. Zuiker, K. B. Hisert, et al., Front Cell Infect Microbiol 14:1275940, 2024, https://doi.org/10.3389/fcimb.2024.1275940 ). A recently developed MEK1/2 inhibitor compound, ATR-002, has been recognized for its ability to exert direct antibacterial effects on gram-positive bacterial species, including S. aureus (C. Bruchhagen, M. Jarick, C. Mewis, T. Hertlein, et al., Sci Rep 8:9114, 2018, https://doi.org/10.1038/s41598-018-27445-7 ). However, whether ATR-002 elicits antibacterial effects on clinically relevant strains of S. aureus or anti-inflammatory effects is unknown. In this study, the effects of ATR-002 on human CF macrophage TLR2-induced pro-inflammatory cytokine secretion were evaluated, demonstrating that ATR-002 reduced TNF-α and IL-8 secretion induced by the TLR2 agonists FSL-1 or Pam3CSK4. The antibacterial effects of ATR-002 were evaluated by minimum inhibitory concentration testing using S. aureus clinical isolates obtained from PwCF. Utilization of a murine methicillin-resistant S. aureus (MRSA) pulmonary infection model further confirmed the in vivo anti-inflammatory and antibacterial effects of ATR-002. Finally, infection of wild-type and Mek2 KO mice revealed that loss of MEK2 was host-protective during MRSA pulmonary infection by reducing neutrophil-mediated inflammation without altering bacterial clearance. In summary, this study highlights the therapeutic potential of targeting the MEK1/2 pathway to combat MRSA pulmonary infections. IMPORTANCE Staphylococcus aureus infections pose a significant burden on global healthcare systems. Community-associated transmission of methicillin-resistant S. aureus (MRSA) and the increasing prevalence of other drug-resistant S. aureus isolates limit therapeutic options to combat this opportunistic pathogen. Infection-induced inflammation is a significant driver of tissue damage, especially in cystic fibrosis pulmonary infections. However, therapeutic strategies that can reduce inflammation without compromising host defense and bacterial clearance mechanisms are lacking. This study investigates the dual anti-inflammatory and antibacterial effects of a MEK1/2 inhibitor as a therapeutic strategy to target both host and pathogen with a single compound. This work also identifies host MEK2 as a specific target that can be modulated to reduce inflammation without impairing host defense against MRSA pulmonary infection. Results from this study can inform future human clinical trials to evaluate the ability of the MEK1/2 inhibitor compound ATR-002 to both combat S. aureus infections and reduce inflammation that accompanies these infections.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".