Preparation of Aaptamine-Loaded Fusogenic Liposomes and Evaluation of Its Enhanced Antibacterial Activity Against MRSA

Abstract

The global threat of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of novel therapeutic strategies. Our previous work identified A7, a marine-derived aaptamine alkaloid, as a potential anti-MRSA agent. However, its clinical translation is limited by poor membrane permeability and unclear antibacterial mechanism. Targeting antimicrobial agents by liposomes may be a valid strategy in the treatment of infections refractory to conventional routes of antimicrobial treatment. Therefore, this study aimed to develop A7-loaded fusogenic liposomes (A7@FLP) as a targeted drug delivery system. Fusogenic liposomes loaded with A7 were produced and characterized, with the objectives of examining their improved cellular penetration, antibacterial activity, and inhibitory mechanism against MRSA. The results showed that FLP was successfully developed with a size 128.9 ± 2.2 nm. A7@FLP exhibited sustained release and significantly enhanced anti-MRSA activity in a dose-dependent manner. It achieved a minimum inhibitory concentration (MIC) of 1 μg/mL, which showed 2-fold improvement over free A7 (2 μg/mL). Further mechanistic studies revealed that A7@FLP damaged bacterial wall and membrane integrity, thereby disrupting cellular physiological functions and triggering oxidative stress-mediated cell death. The antibacterial effect was found to be multitargeted, involving oxidative stress, lipid peroxidation, membrane damage, and energy metabolism dysfunction. In conclusion, these findings affirm that A7-loaded fusogenic liposomes represent a highly promising therapeutic candidate for combating MRSA infections.