Iminocarbamoyl-hybridized nitrofuranylcoumarins as broad-spectrum antibacterial agents with multitargeting potential

In this work, a unique type of iminocarbamoyl-hybridized nitrofuranylcoumarins (INs) with multitargeting broad-spectrum antibacterial potential was developed. Most of INs exhibited potent antibacterial potency against the tested bacterial strains; Especially, IN 6a displayed strong activities against MRSA and Klebsiella pneumoniae (MICs = 0.03 and 0.06 μg/mL), being 32- and 16-fold more effective than ciprofloxacin. The highly active IN 6a demonstrated favorable druggability without obvious resistance, hemolysis and cytotoxicity, as well as rapid bactericidal ability. Preliminary mechanistic studies revealed that IN 6a could not only disrupt cell membranes, but also cause the accumulation of reactive oxygen species, which led to metabolic disruption and bacterial death. Moreover, IN 6a could bind with DNA gyrase through various noncovalent interactions, thereby affecting its normal function and inducing cell death. Furthermore, IN 6a displayed superior anti-MRSA efficacy to nifuroxazide and norfloxacin in vivo. These findings suggested that INs are promising multitargeting antibacterial agents to combat global bacterial resistance.