Drug Repurposing by Siderophore Conjugation: Synthesis and Biological Evaluation of Siderophore‐Methotrexate Conjugates as Antibiotics

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  • Sheng Zhao
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Zhi‐Peng Wang
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Zihua Lin
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Guoxing Wei
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Xumei Wen
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Siyu Li
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Xiaohong Yang
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Qun Zhang
    Medicine Laboratory Children's Hospital of Chongqing Medical University Ministry of Education Key Laboratory of Child Development and Disorders 136 Zhongshan 2nd Rd Yuzhong, Chongqing 400014 P. R. China
  • Chunmei Jing
    Medicine Laboratory Children's Hospital of Chongqing Medical University Ministry of Education Key Laboratory of Child Development and Disorders 136 Zhongshan 2nd Rd Yuzhong, Chongqing 400014 P. R. China
  • Yuanwei Dai
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Jian Guo
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China
  • Yun He
    Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University Chongqing 401331 P. R. China

抄録

<jats:title>Abstract</jats:title><jats:p>Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct “Trojan horse” antibacterials. The most potent conjugate <jats:bold>8</jats:bold> with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00×10<jats:sup>3</jats:sup>‐fold improved activity against Gram‐positive <jats:italic>Streptococcus pneumoniae</jats:italic> (<jats:italic>S. pneumoniae</jats:italic>) and Gram‐negative <jats:italic>Yersinia enterocolitica</jats:italic> (<jats:italic>Y. enterocolitica</jats:italic>) compared with Mtx, while possessing 2.31×10<jats:sup>3</jats:sup>‐fold reduced human cytotoxicity, resulting in 2.08×10<jats:sup>6</jats:sup>‐fold improvements in the therapeutic index. This proof‐of‐principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs.</jats:p>

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