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

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

Affiliations

  • 1 College of Pharmaceutical Science & Jianxing Honors College, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address: cjw983617@zjut.edu.cn.
  • 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: hongw@zjut.edu.cn.
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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