Phylogenomics-driven metalloantibiotic engineering: Overcoming ciprofloxacin resistance in Pseudomonasaeruginosa with sideromycin-bismuth synergy.

Antimicrobial resistance exacerbates the difficulty of clinical bacterial infection treatment, as single-target antibiotics rapidly lose efficacy shortly post-clinical use. Such resistance highlights an urgent need for multitargeted therapeutics. Metalloantibiotics, combining metal ions with antimicrobials to disrupt diverse bacterial pathways, represent a promising strategy to circumvent resistance. Here, we engineer a sideromycin-bismuth molecular nanoassembly for treating ciprofloxacin-resistant Pseudomonas aeruginosa. Using phylogenomics-driven methods, we identify four hydroxamate siderophores from Streptomyces fradiae and rationally design sideromycin 7 by a structure-based strategy. Sideromycin 7 forms a 7-Bi3+ coordination complex with bismuth citrate, exerting a three-pronged antibacterial mode of action: direct DNA binding to induce damage and arrest replication, suppression of KdpC synthesis to block KdpFABC-mediated potassium transport, and inhibition of ATP production. In murine models, this combination therapy exhibits potent efficacy against ciprofloxacin-resistant P. aeruginosa with a considerable safety index. Our findings highlight the potential of phylogenomics-guided metalloantibiotic engineering for overcoming drug resistance.