Inhalable bacteriophage endolysins: a novel therapeutic strategy for drug-resistant bacterial pulmonary infections – a comprehensive review

Background Pulmonary infections caused by multidrug-resistant (MDR) bacteria pose a severe global health threat with high mortality rates, especially in hospital-acquired pneumonia. The stagnation of new antibiotic development underscores the urgent need for alternative therapeutics.Methods This review summarizes recent advances in the application of bacteriophage endolysins against major MDR respiratory pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. We focus on their mechanisms of action, synergistic effects with antibiotics, and efficacy against biofilms.Results Endolysins demonstrate potent and species-specific lytic activity against a broad spectrum of MDR bacteria. A key advantage is their low propensity for inducing resistance. Critically, when administered via optimized inhalation delivery systems, endolysins can achieve high local concentrations in the lungs – though this depends on factors such as the aerosol device, formulation properties and patient-related variables – effectively eradicating pathogens in animal models of pneumonia with minimal systemic toxicity. This direct pulmonary delivery approach bypasses many challenges associated with systemic administration and enhances therapeutic outcomes.Conclusion Endolysins represent a promising paradigm shift in combating drug-resistant bacterial pulmonary infections. Their rapid lytic activity, synergy with conventional antibiotics, and suitability for inhalable formulation position them as a potent adjunct or alternative therapy. While challenges in stabilization and large-scale production remain, advancing inhalation delivery systems for endolysins holds immense potential to holds immense potential to revolutionize the treatment of recalcitrant respiratory infections.