Modulation of antimicrobial activity by liposomal antibiotics for the treatment of Pseudomonas aeruginosa isolated from cystic fibrosis patients: potential role of the efflux pump inhibitor Phenylalanine Arginine-β-Naphthylamide

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease that stems from mutations in the CF transmembrane conductance regulator (CFTR) gene. Chronic pulmonary infections are the main cause of death observed in patients with CF, as they can bring about pulmonary exacerbations, inflammation and eventually lung and respiratory failure. Eradication of Pseudomonas aeruginosa, the principal pathogen found in CF patients, is extremely challenging due to its numerous resistance mechanisms, namely efflux pumps and reduced permeability. In the race against antibiotic resistance, there is a pressing need to develop new ways to revive existing antimicrobials and enhance their activity. Indeed, liposomal formulations of antibiotics were shown to revitalize the drugs by increasing their activity against pathogens and reducing associated toxicity. Similarly, phenylalanine arginine-β-naphthylamide (PABN) is a potent efflux pump inhibitor that demonstrated great activity against bacteria like P. aeruginosa by inhibiting drug efflux. In this study, liposomal gentamicin and erythromycin were prepared with the dehydrationrehydration vesicle method and their effects on biofilm formation, quorum sensing, virulence factors production and motility in the presence and absence of PABN were evaluated against clinical and laboratory isolates of P. aeruginosa. Liposomes and PABN combinations potentiated antibiotics and reduced the production of biofilms, virulence factors and motility in the bacteria. These results indicate that both liposomal gentamicin and erythromycin combined with PABN show good promise in keeping P. aeruginosa infections under control in CF lung infections.