Abstract
Antimicrobial resistance is a rising major global health threat. The World Health Organization has placed resistant Pseudomonas aeruginosa on its list of critical priority pathogens.This opportunistic bacterium drives severe lung infections in cystic fibrosis, COPD and ventilated patients, combining multidrug resistance with extensive tissue-destructive capacity. Beyond antibiotic resistance, P. aeruginosa actively induces ferroptosis, an iron-dependent lipid peroxidation-driven form of regulated cell death, via virulence factors such as lipoxygenases (pLoxA) and Pseudomonas quinolone signal (PQS), promoting epithelial barrier breakdown and macrophage dysfunction. This project proposes a host-directed therapeutic strategy targeting ferroptosis to preserve lung tissue integrity and innate immune function without exerting bactericidal pressure. We will first establish and validate in vitro and in vivo infection models to quantify ferroptosis during P. aeruginosa infection and we will then design, synthesize and characterize a novel class of drug-like 1,4-naphthoquinone ferroptosis inhibitors with a distinct mechanism of action. By shifting from pathogen killing to host resilience modulation, this approach aims to complement antibiotics, reduce infection-induced tissue damage and minimize resistance development. The project will establish ferroptosis inhibition as a new avenue for adjunctive treatment of drug-resistant bacterial pneumonia.
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