Multitarget Antibacterial Activity of Novel Aryl-Urea Derivatives Against Vancomycin- and Carbapenem-Resistant Nosocomial Pathogens.

Multidrug-resistant (MDR) nosocomial pathogens represent a critical global health challenge, necessitating the development of novel multitarget antibacterial agents. In this study, a new series of aryl-urea derivatives incorporating uracil and perfluorophenyl moieties were synthesized and structurally characterized using NMR, IR, and elemental analyses. Among the synthesized compounds, perfluorophenyl-based derivatives (compounds 4 and 5) exhibited potent antibacterial activity against vancomycin-resistant Enterococcus faecalis and carbapenem-resistant Acinetobacter baumannii, with low minimum inhibitory concentration (MIC) values. Mechanistic investigations revealed that these compounds significantly inhibited biofilm formation (> 50%), approaching the efficacy of ciprofloxacin, highlighting their strong anti-virulence potential. Notably, both compounds induced a marked increase in intracellular reactive oxygen species (ROS), suggesting oxidative stress-mediated bacterial killing. Furthermore, molecular analyses demonstrated substantial down-regulation of DNA gyrase (gyrA) expression, alongside significant suppression of key virulence genes, including OmpA in A. baumannii and GelE in E. faecalis. Importantly, the integration of oxidative stress induction, DNA topology disruption, and virulence attenuation establishes a coordinated multitarget mechanism underlying the antibacterial efficacy of these compounds. Collectively, this study introduces perfluorophenyl aryl-urea derivatives as promising next-generation antibacterial candidates with dual bactericidal and antivirulence activities, offering a strategic advantage for combating MDR nosocomial infections and warranting further preclinical development.