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Targeting the MEK1/2 pathway to combat Staphylococcus aureus infection and inflammation in cystic fibrosis

Eryn Zuiker1,2,3, Gregory Serpa1,2,3, Mithu De1,3

  • 1Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Mbio
|May 27, 2025
PubMed

Insights

A new MEK1/2 inhibitor, ATR-002, shows promise in treating Staphylococcus aureus infections in cystic fibrosis patients by reducing inflammation and directly killing bacteria. Targeting MEK2 also protects hosts from infection without hindering bacterial clearance.

Area of Science:

  • Immunology and Microbiology
  • Pharmacology and Drug Discovery

Background:

  • Staphylococcus aureus infections, particularly multidrug-resistant strains, are a major challenge for people with cystic fibrosis (PwCF).
  • Infection-induced inflammation exacerbates lung damage in PwCF, and current therapies lack the ability to reduce inflammation without compromising host defense.
  • Previous studies indicated anti-inflammatory effects of MEK1/2 inhibitors in PwCF models.

Purpose of the Study:

  • To evaluate the anti-inflammatory and antibacterial effects of the MEK1/2 inhibitor ATR-002 on Staphylococcus aureus.
  • To investigate ATR-002's impact on pro-inflammatory cytokine secretion in CF macrophages.
  • To assess ATR-002's efficacy against clinical S. aureus isolates from PwCF and in a murine MRSA pulmonary infection model.

Main Methods:

  • Assessed ATR-002's effect on TNF-α and IL-8 secretion in human CF macrophages stimulated with TLR2 agonists.
  • Determined minimum inhibitory concentrations (MICs) of ATR-002 against S. aureus clinical isolates from PwCF.
  • Evaluated in vivo anti-inflammatory and antibacterial effects of ATR-002 in a murine MRSA pulmonary infection model and analyzed host MEK2's role.

Main Results:

  • ATR-002 significantly reduced TNF-α and IL-8 secretion in CF macrophages.
  • ATR-002 demonstrated antibacterial activity against S. aureus clinical isolates.
  • In vivo studies confirmed ATR-002's anti-inflammatory and antibacterial effects in a murine MRSA infection model; MEK2 deficiency was host-protective by reducing inflammation without affecting bacterial clearance.

Conclusions:

  • ATR-002 exhibits dual anti-inflammatory and antibacterial properties, highlighting its therapeutic potential for Staphylococcus aureus infections, especially in cystic fibrosis.
  • Targeting the MEK1/2 pathway, specifically MEK2, offers a strategy to mitigate infection-induced inflammation without compromising bacterial clearance.
  • These findings support further clinical investigation of ATR-002 for treating S. aureus infections and associated inflammation.
Keywords:
MEK1/2Staphylococcus aureuscystic fibrosismacrophages

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