Unlocking the Antibacterial Potential of Naphthalimide-Coumarins to Overcome Drug Resistance with Antibiofilm and Membrane Disruption Ability against Escherichia coli

Resistance by bacteria to available antibiotics is a threat to human health, which demands the development of new antibacterial agents. Considering the prevailing conditions, we have developed a library of new naphthalimide-coumarin moieties as broad-spectrum antibacterial agents to fight against awful drug resistance. Preliminary studies indicate that compounds 8e and 8h display excellent antibacterial activity against Escherichia coli, exceeding the performance of marketed drug amoxicillin. These drug candidates effectively inhibit biofilm formation and disrupt the biofilm virulence factor, which is accountable for the formation of strong biofilm. In addition to this, both compounds exhibit fast bactericidal properties, thus shortening the time of treatment and resisting the emergence of drug resistance for up to 20 passages. Further, biofunctional evaluation reveals that both compounds effectively disrupt the membrane, causing the leakage of cytoplasmic contents and loss in metabolic activity. Both compounds 8e and 8h efficiently induce the ROS, leading to the oxidation of GSH to GSSG, decreasing the GSH activity of the cell, and causing oxidative damage to the cells. Additionally, both compounds effectively bind with DNA to block DNA replication and form supramolecular complexes, thus exhibiting antibacterial activity. Moreover, these compounds readily bind human serum albumin with high binding constants and can be transported to the target site easily. These findings reveal that newly synthesized naphthalimide-coumarin conjugates have the potential to build as potent antibacterial agents and can be used further for clinical trials.