Long Hydrophilic-and-Cationic Polymers: A Different Pathway toward Preferential Activity against Bacterial over Mammalian Membranes

Abstract

We show that simply converting the hydrophobic moiety of an antimicrobial peptide (AMP) or synthetic mimic of AMPs (SMAMP) into a hydrophilic one could be a different pathway toward membrane-active antimicrobials preferentially acting against bacteria over host cells. Our biostatistical analysis on natural AMPs indicated that shorter AMPs tend to be more hydrophobic, and the hydrophilic-and-cationic mutants of a long AMP experimentally demonstrated certain membrane activity against bacteria. To isolate the effects of antimicrobials' hydrophobicity and systematically examine whether hydrophilic-and-cationic mutants could inherit the membrane activity of their parent AMPs/SMAMPs, we constructed a minimal prototypical system based on methacrylate-based polymer SMAMPs and compared the antibacterial membrane activity and hemolytic toxicity of analogues with and without the hydrophobic moiety. Antibacterial assays showed that the hydrophobic moiety of polymer SMAMPs consistently promoted the antibacterial activity but diminished in effectiveness for long polymers, and the resultant long hydrophilic-and-cationic polymers were also membrane active against bacteria. What distinguished these long mutants from their parent SMAMPs were their drastically reduced hemolytic toxicities and, as a result, strikingly enhanced selectivity. Similar toxicity reduction was observed with the hydrophilic-and-cationic mutants of long AMPs. Taken together, our results suggest that long hydrophilic-and-cationic polymers could offer preferential membrane activity against bacteria over host cells, which may have implications in future antimicrobial development.

Copolymers of acrylonitrile with quaternizable thiazole and triazole side-chain methacrylates as potent antimicrobial and hemocompatible systems

“…2E) [35]. This result agrees well with recently reported examples showing that hydrophilicity diminishes hemotoxicity and then increases selectivity [64,66,[72][73][74][75][76][77]. However, there has to be a correct balance between the hydrophilic and hydrophobic segments, since it has been also reported that the increase on hydrophobicity can lead to lower hemocytotoxicity [78,79].…”

Controlling macromolecular structures towards effective antimicrobial polymers

“…In another study, antimicrobial random copolymers with improved selectivities were developed by them. They used hydrophilic and cationic methacrylate repeating units in the polymers (Table 1F) [75]. Kuroda et al designed novel cationic antimicrobial polymers that can self-degrade via intramolecular amidation reactions [76].…”

“…[113,114]. polymers is reported in several recent studies as a measure of overall amphiphilic balance [75,124]. It is observed that the amphiphilicity of polymers is influenced by the chemical structure, size or length of hydrophobic group, as well as its location on the polymer chain.…”

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

“…Similar results were observed for poly(norbornene) copolymers when extended by either zwitterionic, sugar or PEG moieties. 31 In the case of polyacrylics, a complete exchange of the hydrophobic component (HEMA 32 or PEGMA 33 ) still results in antimicrobial polymers. However, it is unclear whether these systems still target the bacterial membrane like other AMP mimics.…”

“…22d For systems, where a hydrophilic component instead of a hydrophobic comonomer is incorporated, an opposite trend is reported (increased antimicrobial activity at higher molar mass). 32 For other polymers (poly(carbonates)) biological activity does not seem to scale with length. 39 It is important in this context to keep in mind that all described systems are polydisperse synthetic polymers.…”