Improved Antibacterial Properties of Pyrazole-Based Water-Soluble Dendrimer Nanoparticles

Pyrazole derivatives represent excellent candidates for meeting the worldwide need for new antimicrobial compounds against MDR bacteria. For this reason, we considered two previously synthesized pyrazoles, namely BBB4 and CR232 , which however were both insoluble in water. To overcome this problem and allow the determination of reliable minimum inhibitory concentrations (MICs), we initially prepared water-soluble and clinically applicable BBB4- and CR232-loaded nanoparticles (BBB4-G4K and CR232-G5K NPs). BBB4-loaded NPs proved to be highly effective against several isolates of Staphylococcus aureus and S. epidermidis, showing MIC values (1.5–3.0 µM) that were 15.5–124.3-fold lower than those obtained for free BBB4 against isolates of the same two species. Even lower MICs (0.36–2.89 µM) were observed for CR232-G5K NPs against all the MDR Gram-positive and Gram-negative clinical isolates considered, including colistin-resistant strains of MDR Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemases (KPCs)-producing K. pneumoniae (0.72 µM). Additionally, in time–kill experiments, CR232-G5K NPs displayed a rapid bactericidal activity with no significant regrowth after 24 h on all MDR strains tested. Conjecturing a clinical use of CR232-G5K and of BBB4-G4 NPs, cytotoxicity experiments on human keratinocytes were performed, determining very favourable selectivity indices for both formulations. Importantly, BBB4 and CR232 released by NPs were 2.5-fold and 10.8-fold less cytotoxic than non-nano-manipulated BBB4 and CR232, respectively. Overall, due to their physicochemical and biological properties, CR232-G5K NPs could represent a new potent weapon to treat infections sustained by many MDR bacteria, while BBB4-G4K NPs could be considered as a promising new therapeutic option against skin infections caused by staphylococci.