The Role of Hydrophobicity in the Antimicrobial and Hemolytic Activities of Polymethacrylate Derivatives

Abstract

We synthesized cationic random amphiphilic copolymers by radical copolymerization of methacrylate monomers with cationic or hydrophobic groups and evaluated their antimicrobial and hemolytic activities. The nature of the hydrophobic groups, and polymer composition and length were systematically varied to investigate how structural parameters affect polymer activity. This allowed us to obtain the optimal composition of polymers suitable to act as non-toxic antimicrobials as well as non-selective polymeric biocides. The antimicrobial activity depends sigmoidally on the mole fraction of hydrophobic groups (fHB). The hemolytic activity increases as fHB increases and levels off at high values of fHB, especially for the high-molecular-weight polymers. Plots of HC50 values versus the number of hydrophobic side chains in a polymer chain for each polymer series showed a good correlation and linear relationship in the log–log plots. We also developed a theoretical model to analyze the hemolytic activity of polymers and demonstrated that the hemolytic activity can be described as a balance of membrane binding of polymers through partitioning of hydrophobic side chains into lipid layers and the hydrophobic collapsing of polymer chains. The study on the membrane binding of dye-labeled polymers to large, unilamellar vesicles showed that the hydrophobicity of polymers enhances their binding to lipid bilayers and induces collapse of the polymer chain in solution, reducing the apparent affinity of polymers for the membranes.

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

“…Modifying the cationic content from primary to tertiary and quaternary ammonium groups reduced antimicrobial activity significantly, with the quaternary ammonium cationic groups displaying no antimicrobial activity. 18 Antimicrobial activity was independent of molecular weight, however, higher molecular weight polymers displayed much increased hemolytic activities. 17a Fig.…”

“…15 Amino ethyl methacrylate was usually used as charge generating unit and copolymerized with methacrylates bearing various hydrophobic side chains (methyl, 16 butyl, 17 ethyl, 18 hexyl 18 and phenyl 18 ) (Fig. 3).…”

“…59 Polymers containing 47% of the hydrophobic methyl methacrylate unit were found to have antimicrobial activity at low micromolar MIC values, and little hemolytic activity. 18 Increasing the hydrophobic balance of the copolymers with longer alkyl chains, such as butyl methacrylate served to increase toxicity, relative to methyl methacrylate-containing copolymers which display the lowest toxicity. Modifying the cationic content from primary to tertiary and quaternary ammonium groups reduced antimicrobial activity significantly, with the quaternary ammonium cationic groups displaying no antimicrobial activity.…”

“…Studies of polymer length and hydrophobic content had concluded that a low molecular weight (MW = 1300 -1900 g/mol) was optimum for antimicrobial activity and toxicity, when combined with a hydrophobic content between 30-40%. 18 When evaluating hydrophobicity (alkyl chain length) for antimicrobial activity, it was found that the C4 alkyl chain gave optimum performance for antibacterial activity at 30% hydrophobic ratio. Shorter alkyl chains required a higher hydrophobic ratio to achieve similar MIC values.…”

“…The group prepared primary, secondary, tertiary and quaternary ammonium salt cationic groups, and found that the primary group provided the highest antimicrobial activities, whilst quaternary ammonium salts were inactive for the poly(methacrylate) series. 18,69 …”