Montelukast treats Streptococcus pneumoniae-induced sepsis via antibacterial and anti-inflammatory activities.

Streptococcus pneumoniae is a leading causative pathogen of community-acquired pneumonia and sepsis. The increasing prevalence of antibiotic resistance among S. pneumoniae strains poses a major challenge to conventional antibiotic therapies. This study aimed to systematically evaluate the antibacterial, anti-biofilm, and in vivo therapeutic effects of montelukast against S. pneumoniae and to explore its potential for drug repurposing as an anti-infective agent. In vitro susceptibility testing revealed that montelukast exhibited inhibitory activity against both standard reference strains and 11 clinical multidrug-resistant (MDR) S. pneumoniae isolates, with minimum inhibitory concentrations (MICs) ranging from 4 to 32 µg/mL. Time-kill assays using the representative MDR strain S12 showed that montelukast at 16 µg/mL could completely eradicate bacteria within 8 h. And biofilm assays further demonstrated that montelukast at concentrations of 8-16 µg/mL significantly disrupted preformed biofilms and reduced viable bacterial counts within mature biofilms, suggesting its potential to combat chronic infections. In a mouse model of sepsis, montelukast treatment significantly improved survival rates of infected mice, with the 10 mg/kg dosage group achieving a 7-day survival rate of 80%. Quantification of bacterial burden revealed a marked reduction in colony-forming units (CFUs) in both blood and lung of montelukast-treated mice. Furthermore, analysis of serum inflammatory cytokines indicated that montelukast effectively suppressed the secretion of pro-inflammatory mediators such as TNF-α and IL-6, suggesting a dual role in infection control and inflammation modulation. In conclusion, montelukast exhibits potent anti-S. pneumoniae activity, including bactericidal effects against resistant strains, biofilm disruption capabilities, and synergistic antibacterial and anti-inflammatory effects in vivo. These findings support the potential repurposing of montelukast as a therapeutic agent for S. pneumoniae infections, particularly sepsis. IMPORTANCE: Montelukast showed promise as a repurposed treatment for multidrug-resistant Streptococcus pneumoniae, especially in severe infections like sepsis. It demonstrated strong in vitro activity against both sensitive and resistant strains and exerted concentration-dependent bactericidal effects and cleared biofilms. In a mouse sepsis model, montelukast improved survival, reduced bacterial load, and mitigated inflammation. Mechanistically, it disrupted membrane integrity and induced oxidative stress and may target pseudouridine synthase. These findings supported montelukast's potential as an antimicrobial with dual antibacterial and anti-inflammatory action.