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 n...

Hydrophilic Modifications of an Amphiphilic Polynorbornene and the Effects on its Hemolytic and Antibacterial Activity

“…21, 23, 32, 35 Selectivity values were improved in the prior cases by fine tuning of these systems by copolymerization. Therefore, to preserve the facial amphiphilicity at the repeat unit level, in this study, monomers composed of the same hydrophobic backbone and varying biocompatible hydrophilic pendant moieties were designed and synthesized (Figure 1).…”

Controlling macromolecular structures towards effective antimicrobial polymers

“…They observed improving antibacterial activities of copolymers with increasing alkyl tail lengths on the phosphonium group. A series of amphiphilic pyridinium copolymers were prepared by Sen and coworkers to compare the spatial relationship between the positive charge and the pendent alkyl tail as well as the effect from the tail length [126]. The polymers were prepared using vinylpyridine and methacrylate monomers via free radical polymerization.…”

Multifunctional Poly(Vinyl Amine)s Bearing Azetidinium Groups: One Pot Preparation in Water and Antimicrobial Properties

“…To understand the effect of cationic modification, the efficacy of three multifunctional PVAm samples having 11% hydrophobic C-10 repeating units and 5, 10 Figure 3, Table S2, Supporting Information).…”

“…Lienkamp et al [9] reported the preparation of a library of homo-and copolymers by a molecular kit approach and showed that the antimicrobial efficacy can be tuned by variation of the hydrophobic/hydrophilic balance. Sambhy et al [10] reported the antimicrobial efficacy of different pyridinium polymers varying the hydrophobic/hydrophilic balance. Westman et al prepared poly(vinyl amine) analogs having alkyl chains of different chain length (C-6 chain, C-8 chain, C-12 chain) and determined their antimicrobial efficacy.…”