Cationic acrylate oligomers comprising amino acid mimic moieties demonstrate improved antibacterial killing efficiency

James Grace, Alysha G Elliott, Johnny X Huang, Elena Katharina Schneider, Nghia Truong Phuoc, Matthew A Cooper, Jian Li, Thomas Davis, John Quinn, Tony Velkov, Michael R Whittaker

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Cu(0)-mediated polymerization was employed to synthesize a library of structurally varied cationic polymers and their application as antibacterial peptide mimics was assessed. Eight platform polymers were first synthesized with low degrees of polymerization (DP) using (2-Boc-amino)ethyl acrylate as the monomer and either ethyl α-bromoisobutyrate or dodecyl 2-bromoisobutyrate as the initiator (thus providing hydrocarbon chain termini of C2 or C12, respectively). A two-step modification strategy was then employed to generate the final sixteen-member polymer library. Specifically, an initial deprotection was employed to reveal the primary amine cationic polymers, followed by guanylation. The biocidal activity of these cationic polymers was assessed against various strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Polymers having a short segment of guanidine units and a C12 hydrophobic terminus were shown to provide the broadest antimicrobial activity against the panel of isolates studied, with MIC values approaching those for Gram-positive targeting antibacterial peptides: daptomycin and vancomycin. The C12-terminated guanidine functional polymers were assayed against human red blood cells, and a concomitant increase in haemolysis was observed with decreasing DP. Cytotoxicity was tested against HEK293 and HepG2 cells, with the lowest DP C12-terminated polymer exhibiting minimal toxicity over the concentrations examined, except at the highest concentration. Membrane disruption was identified as the most probable mechanism of bacteria cell killing, as elucidated by membrane permeability testing against E. coli.

Original languageEnglish
Pages (from-to)531-536
Number of pages6
JournalJournal of Materials Chemistry B
Volume5
Issue number3
DOIs
Publication statusPublished - 2017

Cite this

Grace, James ; Elliott, Alysha G ; Huang, Johnny X ; Schneider, Elena Katharina ; Truong Phuoc, Nghia ; Cooper, Matthew A ; Li, Jian ; Davis, Thomas ; Quinn, John ; Velkov, Tony ; Whittaker, Michael R. / Cationic acrylate oligomers comprising amino acid mimic moieties demonstrate improved antibacterial killing efficiency. In: Journal of Materials Chemistry B. 2017 ; Vol. 5, No. 3. pp. 531-536.
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abstract = "Cu(0)-mediated polymerization was employed to synthesize a library of structurally varied cationic polymers and their application as antibacterial peptide mimics was assessed. Eight platform polymers were first synthesized with low degrees of polymerization (DP) using (2-Boc-amino)ethyl acrylate as the monomer and either ethyl α-bromoisobutyrate or dodecyl 2-bromoisobutyrate as the initiator (thus providing hydrocarbon chain termini of C2 or C12, respectively). A two-step modification strategy was then employed to generate the final sixteen-member polymer library. Specifically, an initial deprotection was employed to reveal the primary amine cationic polymers, followed by guanylation. The biocidal activity of these cationic polymers was assessed against various strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Polymers having a short segment of guanidine units and a C12 hydrophobic terminus were shown to provide the broadest antimicrobial activity against the panel of isolates studied, with MIC values approaching those for Gram-positive targeting antibacterial peptides: daptomycin and vancomycin. The C12-terminated guanidine functional polymers were assayed against human red blood cells, and a concomitant increase in haemolysis was observed with decreasing DP. Cytotoxicity was tested against HEK293 and HepG2 cells, with the lowest DP C12-terminated polymer exhibiting minimal toxicity over the concentrations examined, except at the highest concentration. Membrane disruption was identified as the most probable mechanism of bacteria cell killing, as elucidated by membrane permeability testing against E. coli.",
author = "James Grace and Elliott, {Alysha G} and Huang, {Johnny X} and Schneider, {Elena Katharina} and {Truong Phuoc}, Nghia and Cooper, {Matthew A} and Jian Li and Thomas Davis and John Quinn and Tony Velkov and Whittaker, {Michael R}",
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Cationic acrylate oligomers comprising amino acid mimic moieties demonstrate improved antibacterial killing efficiency. / Grace, James; Elliott, Alysha G; Huang, Johnny X; Schneider, Elena Katharina; Truong Phuoc, Nghia; Cooper, Matthew A; Li, Jian; Davis, Thomas; Quinn, John; Velkov, Tony; Whittaker, Michael R.

In: Journal of Materials Chemistry B, Vol. 5, No. 3, 2017, p. 531-536.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Cationic acrylate oligomers comprising amino acid mimic moieties demonstrate improved antibacterial killing efficiency

AU - Grace, James

AU - Elliott, Alysha G

AU - Huang, Johnny X

AU - Schneider, Elena Katharina

AU - Truong Phuoc, Nghia

AU - Cooper, Matthew A

AU - Li, Jian

AU - Davis, Thomas

AU - Quinn, John

AU - Velkov, Tony

AU - Whittaker, Michael R

PY - 2017

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AB - Cu(0)-mediated polymerization was employed to synthesize a library of structurally varied cationic polymers and their application as antibacterial peptide mimics was assessed. Eight platform polymers were first synthesized with low degrees of polymerization (DP) using (2-Boc-amino)ethyl acrylate as the monomer and either ethyl α-bromoisobutyrate or dodecyl 2-bromoisobutyrate as the initiator (thus providing hydrocarbon chain termini of C2 or C12, respectively). A two-step modification strategy was then employed to generate the final sixteen-member polymer library. Specifically, an initial deprotection was employed to reveal the primary amine cationic polymers, followed by guanylation. The biocidal activity of these cationic polymers was assessed against various strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Polymers having a short segment of guanidine units and a C12 hydrophobic terminus were shown to provide the broadest antimicrobial activity against the panel of isolates studied, with MIC values approaching those for Gram-positive targeting antibacterial peptides: daptomycin and vancomycin. The C12-terminated guanidine functional polymers were assayed against human red blood cells, and a concomitant increase in haemolysis was observed with decreasing DP. Cytotoxicity was tested against HEK293 and HepG2 cells, with the lowest DP C12-terminated polymer exhibiting minimal toxicity over the concentrations examined, except at the highest concentration. Membrane disruption was identified as the most probable mechanism of bacteria cell killing, as elucidated by membrane permeability testing against E. coli.

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SN - 2050-750X

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