Angewandte Chemie International Edition · 2022 · 32 citations · 25 references
PharmacyMedicinal ChemistryPharmacologyAntimicrobial ResistanceDrug DiscoveryDrug RepurposingAntibacterial PharmacologyAntibacterial ResistanceAntibacterial TherapyAntibiotic ResistanceConjugation ReactionsResistance In Gram-negative BacteriaAntibacterial Drug DevelopmentAntibacterial Drug RepurposingAnticancer ActivityAntimicrobial Drug RepurposingConjugationNovel Antibacterial AgentsNovel Antibacterial Drug DiscoveryProdrug-drug Conjugates
Abstract 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.
25
Wilma Neumann, Martina Sassone‐Corsi, Manuela Raffatellu et al. · Journal of the American Chemical Society · 2018 · 144 citations · Full text
Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens
Zihua Lin, Xiaobo Xu, Sheng Zhao et al. · Nature Communications · 2018 · 101 citations · Full text