Investigation of polymyxin-induced pulmonary toxicity using systems pharmacology and chemical biology approaches

Multidrug-resistant lung infections pose a growing global health threat, often leaving physicians with few effective treatment options. Polymyxins are last-resort antibiotics used against Gram-negative ‘superbugs’, but their clinical use via inhalation is limited by lung toxicity. This research reveals how polymyxins enter lung cells and trigger iron-dependent oxidative damage. Importantly, the study shows that even minor chemical modifications to polymyxins can substantially reduce lung toxicity while preserving antibacterial activity. This study advances understanding of polymyxin-associated lung toxicity and identifies a critical pathway for developing safer inhaled antibiotics to treat life-threatening bacterial lung infections.