Synthesis and Bioactivity of Polymer‐Based Synthetic Mimics of Antimicrobial Peptides (SMAMPs) Made from Asymmetrically Disubstituted Itaconates

Abstract

A series of asymmetrically disubstituted diitaconate monomers is presented. Starting from itaconic anhydride, functional groups could be placed selectively at the two nonequivalent carbonyl groups. By using 2D NMR spectroscopy, it was shown that the first functionalization step occurred at the carbonyl group in the β position to the double bond. These monomers were copolymerized with N,N-dimethylacrylamide (DMAA) to yield polymer-based synthetic mimics of antimicrobial peptides (SMAMPs). They were obtained by free radical polymerization, a metal-free process, and still maintained facial amphiphilicity at the repeat unit level. This eliminates the need for laborious metal removal and is advantageous from a regulatory and product safety perspective. The poly(diitaconate-co-DMAA) copolymers obtained were statistical to alternating, and the monomer feed ratio roughly matched that of the repeat unit content of the copolymers. Investigations of varied R group hydrophobicity, repeat unit ratio, and molecular mass on antimicrobial activity against Escherichia coli and on compatibility with human keratinocytes showed that the polymers with the longest R groups and lowest DMAA content were the most antimicrobial and hemolytic. This is in agreement with the biological activity of previously reported SMAMPs. Thus, the design concept of facial amphiphilicity has successfully been transferred, but the selectivity of these polymers for bacteria over mammalian cells still needs to be optimized.

Biomass-Derived Production of Itaconic Acid as a Building Block in Specialty Polymers

“…Asymmetrically disubstituted diitaconate monomers copolymerized with dimethyl acrylamide propose an encouraging material against bacterial infections as synthetic mimics of these antimicrobial peptides. The easily polymerized IA is a harmless and ecological source that can also prevent bacterial contamination [172]. The polymers mentioned above are relatively cheap (synthesized by metal-free initiator systems), but further structural optimization is still in progress.…”

Progress in the Free and Controlled Radical Homo‐ and Co‐Polymerization of Itaconic Acid Derivatives: Toward Functional Polymers with Controlled Molar Mass Distribution and Architecture

“…These amphiphilic, low molar mass polymers had a cationic ammonium substituent and a hydrophobic substituent on each repeat unit, and were active against the model bacteria Escherichia coli and Staphylococcus aureus . [ 10 ] Surface‐coatings obtained from the zwitterionic poly( N ‐(2‐ammonium ethyl)itaconamic acid) were strongly protein repellent, antimicrobially active, and cell compatible. [ 9 ] Fluorescently labeled polymers were obtained by FRP of itaconic anhydride, followed by functionalization with glycosamines.…”

“…[ 9 ] Further substitution yields diitaconates or diitaconamides (Figure 1d) with either two identical or two different R groups. [ 10,11 ] Disubstituted derivatives of itaconic acid with different substituents are particularly interesting, as they yield polymers with a built‐in, locally precisely balanced stoichiometry of the two functional groups. Such polymers are not accessible by co‐polymerization of acrylic or methacrylic monomers due to the statistical nature of these polymerizations.…”

“…In the biomedical field, monosubstituted itaconamides carrying one ammonium group are an interesting synthetic platform for bioactive poly(carboxyzwitterions), [ 9 ] and asymmetrically substituted diitaconates with one hydrophilic and one hydrophobic group per monomer give access to amphiphilic polymers with tunable antimicrobial activity. [ 10,11 ]…”

Amphiphilic water soluble cationic ring opening metathesis copolymer as an antibacterial agent

“…Major limitation of such antimicrobial peptides are high manufacturing costs, short term antimicrobial ability and decomposition because of their low chemical stability under physiological condition . Whereas, synthetic polymer‐based mimic host defense peptides are generally more robust in physiological condition, easy to synthesize. It is also expected that they do not exhibit drug resistance like conventional antibiotics due to their membrane disruption mechanism .…”