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With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-pos. and Gram-neg. bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound I showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, I showed no inhibitory effect on Gram-neg. bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that I functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that I not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.
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