The rise of antimicrobial resistance (AMR) necessitates alternative strategies. This study investigates the synergistic effects of cefiderocol (a sideromycin) and metallodrugs (e.g., colloidal bismuth citrate, CBS) against drug-resistant Gram-negative bacteria, specifically *Pseudomonas aeruginosa* and *Burkholderia cepacia*. CBS enhances cefiderocol's efficacy against biofilm formation, suppresses resistance development, and resensitizes resistant strains. In a murine pneumonia model, CBS-cefiderocol co-therapy significantly improved survival and reduced bacterial lung burden. This synergy is partly due to Bi³⁺ competing with Fe³⁺ for binding to cefiderocol, increasing Bi³⁺ uptake and reducing Fe³⁺ levels.

Chenyuan Wang, Yushan Xia, Runming Wang, Jingru Li, Chun-Lung Chan, Richard Yi-Tsun Kao, Patrick H. Toy, Pak-Leung Ho, Hongyan Li, Hongzhe Sun