Discovery of coumarin-conjugated hydrazonoindoles as new type of potential antibacterial agents

The global emergence and spread of bacterial resistance pose an urgent task for unique structural type of antibacterial drugs. This work developed a unique type of coumarin-conjugated hydrazonoindoles (CCHs) with large potential to conquer the multidrug-resistant bacteria through multitargeting antibacterial effects. Bioactivity identified hydroxyethyl CCH 8c as a potent antibacterial member with a low MIC (1 μg/mL) against Staphylococcus aureus ATCC 25923. CCH 8c exhibited biosafety, rapid bactericidal activity, and low resistant propensity. Moreover, CCH 8c could not only damage membrane integrity and block the replication of DNA by intercalation, but also make reactive oxygen species burst and weaken lactate dehydrogenase activity. Molecular docking study preliminarily revealed that CCH 8c was able to bind to the active pocket in lactate dehydrogenase by the noncovalent interactions like hydrogen bonds and π-cation to inhibit enzymatic function. The multitargeting antibacterial behavior might result in CCH 8c to exhibit low resistance. These findings implied that CCH 8c as a promising multitargeting antibacterial candidate deserved further exploration.