Pseudomonas aeruginosa (P. aeruginosa) infections are increasingly challenging due to their propensity to form biofilms and low outer membrane permeability, especially in chronically infected patients with thick mucus. P. aeruginosa exhibits multiple drug resistance mechanisms, making it one of the most significant global public health threats. In this study, we found that moxifloxacin (MXC) and antibacterial peptides (ε-poly-l-lysine, ε-PLL) exhibited a synergistic effect against multidrug-resistant P. aeruginosa (MDR-P. aeruginosa). MXC was combined with ε-PLL to prepare lipase-responsive nanoparticles (MCIP/(PEG-PCL)/PLL NPs) with a weakly negative charge. The weakly negatively charged MCIP/(PEG-PCL)/PLL NPs demonstrated remarkable mucus and biofilm penetration capabilities, thereby overcoming one of the adaptive drug resistance mechanisms. MCIP/(PEG-PCL)/PLL NPs improved the outer and inner membrane permeability and inhibited the expression of the efflux pump MexAB-OprM gene in MDR-P. aeruginosa, thereby overcoming mechanisms of both intrinsic and acquired drug resistance. Meanwhile, the nanoparticles demonstrated an ability to reduce repeated infections with MDR-P. aeruginosa. Additionally, the bacterial burden in the lungs of mice treated with MCIP/(PEG-PCL)/PLL NPs was significantly lower than that in the MXC group, resulting in a 99% clearance rate. Notably, MCIP/(PEG-PCL)/PLL NPs showed no toxicity toward BEAS-2B cells or RAW 267.4 cells, nor did they adversely affect pulmonary function or major organs. This study demonstrated the potential of the nanodrug delivery system composed of the antibiotic moxifloxacin and the antibacterial peptide ε-PLL in addressing the clinical challenges of treating chronic pulmonary infections caused by MDR-P. aeruginosa.
Keywords: MexAB-OprM gene; biofilms and mucus; moxifloxacin; multidrug-resistant Pseudomonas aeruginosa; outer membrane permeability.