Antibacterial and Hemolytic Activities of Pyridinium Polymers as a Function of the Spatial Relationship between the Positive Charge and the Pendant Alkyl Tail

Abstract

Synthetic amphiphilic polymers that mimic the membranedisrupting properties of natural antimicrobial peptides [1] show potent biocidal activity towards bacteria, [2][3][4] fungi, [5] and viruses. [6] Their easy synthesis, stability towards enzymatic degradation, and facile chemical tailoring make them promising candidates as novel chemical disinfectants and nonleaching biocides for a variety of biomedical applications. However, there is a delicate balance between useful biocidal activity and detrimental toxicity towards mammalian cells. Herein, we report the interplay between the chemical structure and antibacterial versus hemolytic properties of amphiphilic pyridinium polymers.The membrane-disrupting activity of amphiphilic polymers is mainly dependent on the charge and hydrophobicity, which have to be optimized to cause membrane disruption. [4,7,8] Structure-activity relationships have previously been reported on the effect of the length of the alkyl tail, an increase in the positive charge, and the overall hydrophobicity/hydrophilicity of the polymer on the membrane-disrupting activity. [7][8][9][10][11][12][13][14] All these variables also influence the balance between the antimicrobial and the hemolytic (toxicity) properties of the amphiphilic polymers. An important, yet unexplored, question is how the activity of an amphiphilic polycation varies as a function of the spatial positioning of the positive charge and the hydrophobic alkyl tail. For example, would the antibacterial and hemolytic activity of a polycation be any different if the positive charge and the alkyl tail were on the same center, as opposed to being spatially separated? We address this and related questions by comparing series of homologous amphiphilic pyridinium polymers that differ only in how the positive charge and the alkyl tail are spatially related. We observe that the spatial positioning of the charge and tail significantly influences the toxicity of these polymers, and this result may be used as a guiding principle in the design of polymeric antimicrobial compounds with reduced toxicity.Two series (A and B) of amphiphilic pyridinium-methacrylate copolymers differing only in the spatial positioning of the positive charge and the alkyl tail were synthesized as shown in Scheme 1. Series A consisted of pyridiniummethacrylate copolymers in which the positive charge and the alkyl tail are on the same center. A copolymer consisting of approximately 50 mol % vinylpyridine (VP) units and about 50 mol % methyl methacrylate (MMA) units was synthesized by radical polymerization. All the pyridine units were then completely N alkylated by heating with an excess of the respective n-iodoalkane. This process yielded six cationic polymers in series A, that is, A 2 , A 3 , A 4 , A 6 , A 8 , and A 10 with alkyl tails that were 2, 3, 4, 6, 8, and 10 carbon atoms long, respectively. Series B consisted of vinylpyridinium-alkyl methacrylate copolymers in which the positive charge and the alkyl tail are on separate centers. Copolymers of VP with different ...

Antimicrobial cationic polymers: from structural design to functional control

“…Apart from the ammonium groups, the iminium structures are another common form of the cationic groups, like pyridinium, [22][23][24][25] imidazolium 26,27 and guanidinium salts. 28,29 The difference between ammonium and iminium groups is that the positive charges of the latter ones are delocalized evenly through the π bonds or aromatic conjugated systems, which may influence their adsorptive ability to membrane.…”

Phosphonium-Functionalized Polymer Micelles with Intrinsic Antibacterial Activity

“…While there is not a complete understanding of all the factors influencing selectivity for eukaryotic and prokaryotic membranes, 46 it is likely that the particular hydrophilichydrophobic balance of the Et 3 P-BCP micelles results in its higher activity against red blood cell membranes. 55 Nevertheless, the overall results suggest that the phosphonium-functionalized micelles have good potential to selectively kill bacteria. While further studies would be required to elucidate the in vitro and in vivo toxicity, previous studies have shown that phosphonium compounds can exhibit low in vitro, 36,56 and in vivo 56 toxicity.…”

Antimicrobial Polymers: Mimicking Amino Acid Functionali ty, Sequence Control and Three-dimensional Structure of Host-defen se Peptides

“…Sen and co-workers adopted this approach to generate a series of random copolymers of 4-vinylpyridine and methacrylates ( Figure 12). 21 Sen prepared three different series via N-alkylation of the pyridinyl group: a) alkyl functionalised pyridinium-methyl methacrylate (same centre); b) methyl functionalised pyridinium-alkyl functionalised methacrylate (different centre); and c) alkyl functionalised pyridinium and methacrylate (same centre). This enabled Sen to compare amphiphilic polymers whose hydrophobic and cationic components were either spatially separated (single pendant; Fig.…”

“…Two series were designed: same centre -whereby the positive charge and alkyl group were on the pyridyl substituent; and separate centre -whereby the positive charge was located on the pyridine (methyl pyridinium ion) and the alkyl group incorporated on the acrylate centre. 21 For both series, MIC values decreased to an optimum alkyl tail length of C4 for E. coli and C6 for B. Figure 23 summaries the different lactam monomers used in these studies.…”

“…21 For one series, methyl methacrylate was copolymerized with cationic pyridinium quaternized by the alkyl chain as the substituent. The other copolymer series contained pyridinium monomer bearing a methyl group and the pendant alkyl chain was attached to the methacrylate units (Fig.…”