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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 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00×10 3 -fold improved activity against Gram-positive Streptococcus pneumoniae (S. pneumoniae) and Gram-negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31×10 3 -fold reduced human cytotoxicity, resulting in 2.08×10 6 -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., (© 2022 Wiley-VCH GmbH.)

There is an urgent need to discover new antibiotics and improve the efficacy of known antibiotics against Gram-negative bacteria. "Trojan horse" conjugates are novel and promising antibiotics. Herein we report the design and synthesis of vitamin-B 12 -ampicillin conjugates, which exhibited more than 500 times improved activity against Escherichia coli compared with ampicillin itself. Our studies demonstrate that the vitamin-B 12 uptake pathway could be employed for effective antibiotic delivery and efficacy enhancement.