Synthesis, Characterization, and Bactericidal Activity of a 4-Ammoniumbuthylstyrene-Based Random Copolymer

Abstract

The growing resistance of bacteria to current chemotherapy is a global concern that urgently requires new and effective antimicrobial agents, aimed at curing untreatable infection, reducing unacceptable healthcare costs and human mortality. Cationic polymers, that mimic antimicrobial cationic peptides, represent promising broad-spectrum agents, being less susceptible to develop resistance than low molecular weight antibiotics. We, thus, designed, and herein report, the synthesis and physicochemical characterization of a water-soluble cationic copolymer (P5), obtained by copolymerizing the laboratory-made monomer 4-ammoniumbuthylstyrene hydrochloride with di-methyl-acrylamide as uncharged diluent. The antibacterial activity of P5 was assessed against several multi-drug-resistant clinical isolates of both Gram-positive and Gram-negative species. Except for strains characterized by modifications of the membrane charge, most of the tested isolates were sensible to the new molecule. P5 showed remarkable antibacterial activity against several isolates of genera Enterococcus, Staphylococcus, Pseudomonas, Klebsiella, and against Escherichia coli, Acinetobacter baumannii and Stenotrophomonas maltophilia, displaying a minimum MIC value of 3.15 µM. In time-killing and turbidimetric studies, P5 displayed a rapid non-lytic bactericidal activity. Due to its water-solubility and wide bactericidal spectrum, P5 could represent a promising novel agent capable of overcoming severe infections sustained by bacteria resistant the presently available antibiotics.

Broad-Spectrum Bactericidal Activity of a Synthetic Random Copolymer Based on 2-Methoxy-6-(4-Vinylbenzyloxy)-Benzylammonium Hydrochloride

“…Therefore, they are also capable of killing MDR isolates rapidly, simply on contact, thus overcoming their acquired ability to resist traditional antibiotics [11,13,[22][23][24]. Interestingly, the MIC values of P7 against Gram-positive isolates were very similar to those obtained by the recently published P5 copolymer [13]. However, differently from what was observed when testing its anti-tumor activity on NB cells, which was lower than that of P5 [20], when tested on bacteria P7 was found to be more cytotoxic than P5 [13], showing both MIC and MBC values very much lower than those of P5.…”

“…Against E. coli, P7 displayed MIC values (µM) that were 2-4 times lower than those of Poly1. Like the cationic antibacterial copolymer, we recently reported [13], P7 was ineffective against a colistin-resistant strain of P. aeruginosa, due to a reduced possibility of electrostatic interactions with the outer membrane of the isolate, caused by an adaptive modification of lipid A [13,37]. Additionally, P7 was found to be more active than a derivative of the potent natural cationic peptide magainin II, known as Ala 8,13,18 -magainin 2 amide, and which has been reported to exhibit potent antimicrobial activity.…”

“…In this context, we recently reported the preparation, physicochemical characterization, and antibacterial properties of a cationic water-soluble copolymer (P5) (Figure 1), obtained by polymerizing the 4-ammoniumbuthylstyrene hydrochloride monomer (M5) with di-methyl acrylamide (DMAA) used as a comonomer [13]. P5 proved to be much more potent than the low-molecular-weight monomer M5 and displayed remarkable antibacterial activity against most of the 61 isolates tested, belonging both to Gram-positive and Gram-negative species [13].…”

“…In that study, we also reported the preparation, physicochemical characterization, and the significant cytotoxic effects of a new watersoluble cationic copolymer (P7) (Figure 2), obtained by polymerizing 2-methoxy-6-(4vinylbenzyloxy)-benzylammonium hydrochloride monomer (M7) with di-methyl acrylamide (DMAA) comonomer [20]. P5 proved to be much more potent than the low-molecular-weight monomer M5 and displayed remarkable antibacterial activity against most of the 61 isolates tested, belonging both to Gram-positive and Gram-negative species [13]. Since it is known that the cytoplasmic membrane of cancer cells, including neuroblastoma (NB) cell lines, is more like that of prokaryotes than that of eukaryotes, and cationic material active on bacteria are selectively cytotoxic also on tumor cells, including multidrug-resistant ones [20,21,25], we recently observed the cytotoxic effects of P5 on two cell lines that were differently sensitive to ETO [20].…”

Antimicrobial Polymeric Structures Assembled on Surfaces

“…They were recently thoroughly reviewed by Alfei and Schito, and therefore, additional information on this topic can be found elsewhere [ 157 ]. We would only like to additionally emphasize the existence of a new water-soluble cationic copolymer synthesized from 4-ammoniumbuthylstyrene hydrochloride and reported only very recently [ 158 ]. This copolymer was shown to be able to display a rapid non-lytic bactericidal activity and thus, to be capable of acting against several bacteria, including E. coli , Acinetobacter baumannii and Stenotrophomonas maltophilia .…”