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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 \u201cTrojan horse\u201d antibacterials. The most potent conjugate <jats:bold>8<\/jats:bold> with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00\u00d710<jats:sup>3<\/jats:sup>\u2010fold improved activity against Gram\u2010positive <jats:italic>Streptococcus pneumoniae<\/jats:italic> (<jats:italic>S. pneumoniae<\/jats:italic>) and Gram\u2010negative <jats:italic>Yersinia enterocolitica<\/jats:italic> (<jats:italic>Y. enterocolitica<\/jats:italic>) compared with Mtx, while possessing 2.31\u00d710<jats:sup>3<\/jats:sup>\u2010fold reduced human cytotoxicity, resulting in 2.08\u00d710<jats:sup>6<\/jats:sup>\u2010fold improvements in the therapeutic index. This proof\u2010of\u2010principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs.<\/jats:p>","DOI":"10.1002\/anie.202204139","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T17:03:15Z","timestamp":1657299795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Drug Repurposing by Siderophore Conjugation: Synthesis and Biological Evaluation of Siderophore\u2010Methotrexate Conjugates as Antibiotics"],"prefix":"10.1002","volume":"61","author":[{"given":"Sheng","family":"Zhao","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research Innovative Drug Research Center School of Pharmaceutical Sciences Chongqing University  Chongqing 401331 P. R. 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