Novel naphthalimide-derived cephalosporins as potential multitargeting anti-MRSA candidates.

A unique type of naphthalimide-derived cephalosporins (NCs) as potential multitargeting antibacterial candidates was developed to address the growing threat of drug-resistant bacteria. Some prepared NCs exhibited potent antibacterial activities, aminothiazolyl oxime NC 47 (MIC = 0.5 μg/mL) showed 16-fold and 4-fold greater potency against MRSA than clinical norfloxacin and cefdinir, respectively. It not only gave low cytotoxicity, hemolysis and drug resistance, but also could inhibit the formation of MRSA biofilm. Further investigations revealed multiple mechanisms of action by NC 47, involving membrane disruption, DNA interaction, and ROS accumulation, leading to metabolic suppression, protein leakage and ultimately bacterial death. Moreover, NC 47 could also bind to the allosteric site of PBP2a, thereby inducing the opening of active site and overcoming classical β-lactam resistance. This series of results implied the large potential of naphthalimide-derived cephalosporins as multitargeting anti-MRSA candidates to combat bacterial infection.