Pyrazole-Based Water-Soluble Dendrimer Nanoparticles as a Potential New Agent against Staphylococci

Abstract

Although the antimicrobial potency of the pyrazole nucleus is widely reported, the antimicrobial effects of the 2-(4-bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4), found to be active against several other conditions, have never been investigated. Considering the worldwide need for new antimicrobial agents, we thought it noteworthy to assess the minimum inhibitory concentration (MICs) of BBB4 but, due to its scarce water-solubility, unequivocal determinations were tricky. To obtain more reliable MICs and to obtain a substance also potentially applicable in vivo, we recently prepared water-soluble, BBB4-loaded dendrimer nanoparticles (BBB4-G4K NPs), which proved to have physicochemical properties suitable for clinical application. Here, with the aim of developing a new antibacterial agent based on BBB4, the BBB4-G4K NPs were tested on several strains of different species of the Staphylococcus genus. Very low MICs (1.5–3.0 µM), 15.5–124.3-fold lower than those of the free BBB4, were observed against several isolates of S. aureus and S. epidermidis, the most pathogenic species of this genus, regardless of their resistance patterns to antibiotics. Aiming at hypothesizing a clinical use of BBB4-G4K NPs for staphylococcal skin infections, cytotoxicity experiments on human keratinocytes were performed; it was found that the nano-manipulated BBB4 released from BBB4-G4K NPs (LD50 138.6 µM) was 2.5-fold less cytotoxic than the untreated BBB4 (55.9 µM). Due to its physicochemical and biological properties, BBB4-G4K NPs could be considered as a promising novel therapeutic option against the very frequent staphylococcal skin infections.

Synthesis and Characterization of Pyrazole-Enriched Cationic Nanoparticles as New Promising Antibacterial Agent by Mutual Cooperation

“…To screen the antibacterial effects of CB1H, we determined its MICs, following the microdilution method according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [ 19 ] and as previously reported [ 10 ].…”

“…Very recently, dendrimer nanoparticles (NPs) loaded with a 3,5-diphenyl pyrazole derivative, namely BBB4 (BBB4-G4K NPs), designed to solve the solubility drawbacks of BBB4 [ 9 ], which is otherwise water-insoluble and not clinically applicable, demonstrated potent antibacterial effects, specifically against Staphylococci [ 10 ]. In particular, BBB4-G4K NPs were active on methicillin-resistant Staphylococcus aureus (MRSA) and S. epidermidis (MRSE), also resistant to linezolid.…”

“…In particular, BBB4-G4K NPs were active on methicillin-resistant Staphylococcus aureus (MRSA) and S. epidermidis (MRSE), also resistant to linezolid. It should be noted that these pathogenic species are particularly difficult to treat, due to their resistance to antibiotics and responsibility for different types of infections, including skin infections, bacteremia, bone infections, endocarditis, food poisoning, pneumonia, and toxic shock syndrome (TSS), a life-threatening condition caused by toxins which are often resistant to antibiotics [ 10 ].…”

Antimicrobial Peptides and Cationic Nanoparticles: A Broad-Spectrum Weapon to Fight Multi-Drug Resistance Not Only in Bacteria

“…In this context, ursolic acid or pyrazole derivatives known to be endowed with several pharmacological activities have been successfully encapsulated in fourth- and fifth-generation cationic dendrimers modified with lysine, obtaining drug-loaded nanocomposites with proven high-water solubility and loading capacity [ 177 , 178 , 179 ]. When tested on bacteria, these nanocomposites displayed potent antibacterial activity, much higher than that of the encapsulated molecules, against Gram-positive MDR isolates of the Staphylococcus [ 180 ] and Enterococcus [ 181 ] genera, regardless of the intrinsic antibacterial effects of the dendrimers used as encapsulating agents. This achievement can be explained assuming that the cationic property of the NPs enveloping the bioactive molecules allowed their accumulation on the surfaces of bacteria and promoted their entry into the cells via pore formation.…”

Enhanced Antibacterial Activity of a Cationic Macromolecule by Its Complexation with a Weakly Active Pyrazole Derivative

“…Biomedicines 2022, 10, x FOR PEER REVIEW 2 of 18 other than those of antibiotics available, and which have a lower propensity to develop resistance [6].…”