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

  • Cell Rep Med. 2026 Mar 17;7(3):102637. doi: 10.1016/j.xcrm.2026.102637.
Jianwei Chen  1 ,  Jiangwei Pan  2 ,  Xingyue Lu  2 ,  Lu Wang  2 ,  Keli Tan  2 ,  Yujie Yue  2 ,  Liting Gu  2 ,  Siqi Wang  2 ,  Minghong Chen  3 ,  Hong Jiang  3 ,  Yu Pan  4 ,  Yuanquan Yu  5 ,  Jianwei Nai  6 ,  Dahong Zhang  7 ,  Hong Wang  8
Affiliations
  • 1. College of Pharmaceutical Science & Jianxing Honors College, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address: [email protected].
  • 2. College of Pharmaceutical Science & Jianxing Honors College, Zhejiang University of Technology, Hangzhou 310014, China.
  • 3. Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou 350007, China.
  • 4. Institute of Microbiology, Heilongjiang Academy of Sciences, Harbin 150010, Heilongjiang, China.
  • 5. The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 6. College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, China.
  • 7. Urology & Nephrology Center, Department of Urology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
  • 8. College of Pharmaceutical Science & Jianxing Honors College, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address: [email protected].
PMID: 41759530 DOI: 10.1016/j.xcrm.2026.102637
Abstract

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.

Keywords
P. aeruginosa; metalloantibiotic; sideromycin; siderophore.
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