Norharmane-Loaded Bacterial Cytoplasmic Membranes-Coated Nanoparticles Synergistically Enhance Polymyxin B Against Pseudomonas aeruginosa Infections by Disrupting Biofilms

Abstract

The emergence of multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) infections, particularly those involving biofilm formation, poses a critical challenge to global healthcare. While polymyxin B (PMB) remains a last-line antibiotic against such infections, its efficacy is severely limited by poor biofilm penetration and adaptive resistance mechanisms. In this study, we developed a biomimetic nanoplatform (PMφ-PLGA-NOR) comprising a poly(lactic-co-glycolic acid) (PLGA) core loaded with norharmane (NOR), coated with PMB-modified P. aeruginosa cytoplasmic membrane (PMφ). This design utilizes the homologous targeting of bacterial membrane components and PMB's affinity for gram-negative pathogens to achieve efficient biofilm penetration. NOR, a βcarboline compound, has been shown to disrupt quorum sensing (QS) by inhibiting PqsA, resulting in significant reduction in biofilm formation. In vitro investigations have demonstrated that PMφ-PLGA-NOR disrupts the integrity of biofilms, thereby enhancing the bactericidal efficacy of PMB by facilitating its deep penetration into the biofilm matrix. In vivo, intraperitoneal administration of Mφ-PLGA-NOR combined with PMB achieved a 2-log reduction in bacterial lung burden. This study underscores the promise of bacterial plasma membrane-based pathogen-mimetic nanoplatforms in potentiating the efficacy of antibiotic adjuvants in conjunction with biofilmpenetrating strategies.