Multidrug-resistant P. aeruginosa (MDR-P. aeruginosa), associated with elevated morbidity, mortality, and readmission rates, presents a formidable challenge to eradication due to its robust resistance to antimicrobial agents and biofilm formation. Herein, self-assembling nanoparticles (NO-PE/PLL NPs) comprised of NO donor-conjugated γ-polyglutamic acid (GSNO-PGA), epsilon-poly-l-lysine (PLL) and colistin were fabricated. The negatively charged NO-PE/PLL NPs exhibited effective penetration through airway mucus, reaching the infection site where GSNO-PGA released NO in response to glutathione within biofilm. PLL worked synergistically with colistin (fractional inhibitory concentration index: 0.281), reducing the minimum inhibitory concentration (MIC) of colistin from 2 to 0.5 μg/mL. Benefiting from this synergistic antibacterial action and NO-mediated biofilm disruption, NO-PE/PLL NPs achieved a 99.99 % eradication rate against MDR-P. aeruginosa biofilms. Additionally, NO-PE/PLL NPs efficiently inhibited endotoxins-stimulated inflammation response. In a chronic pulmonary infection model, NO-PE/PLL NPs displayed the highest eradication efficiency (99.78 %) to infected mice, while having no adverse effects on their major organs or pulmonary functions. These results highlight NO-PE/PLL NPs as a promising therapeutic strategy for treating recalcitrant infections caused by MDR-P. aeruginosa biofilms.
Keywords: Colistin; MDR-P. aeruginosa; Nitric oxide; Polymeric nanoparticle; Pulmonary infection.
Copyright © 2024 Elsevier B.V. All rights reserved.