Revolutionizing antibiotic therapy: Polymyxin B and Fe2+-enriched liposomal carrier harness novel bacterial ferroptosis mechanism to combat resistant infections.

To address the pressing issue of bacterial resistance, antibiotics with new mechanisms were urgently needed; yet, the majority of efforts centered on discovering novel structural compounds, often plagued by lengthy research timelines and unpredictability. In this study, we introduce an alternative strategy that rejuvenates outdated antibiotics through a unique delivery system. Specifically, we leveraged polymyxin B (PMB) and created a liposomal carrier encapsulating PMB and Fe2+, designated P/Fe@L-P. When administered to PMB-resistant Acinetobacter baumannii, P/Fe@L-P triggered a downregulation of Nrf2 and GPX4 proteins, accompanied by a significant surge in reactive oxygen species and malondialdehyde levels, signifying the induction of ferroptosis. This mechanism imparted potent antibacterial activity, with P/Fe@L-P achieving minimal inhibitory and bactericidal concentrations of 54 and 192 μM, respectively, outperforming free PMB (72 and 768 μM). In vivo evaluations in mice models further validated the superior efficacy of P/Fe@L-P over PMB in treating PMB-resistant Acinetobacter baumannii pneumonia. This work establishes a highly effective and practical "old drug, new trick" paradigm, potentially expediting the fight against the escalating threat of bacterial resistance.