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WIREs Nanomed Nanobiotechnol
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Antimicrobial polymers as synthetic mimics of host‐defense peptides

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Abstract Antibiotic‐resistant bacteria ‘superbugs’ are an emerging threat to public health due to the decrease in effective antibiotics as well as the slowed pace of development of new antibiotics to replace those that become ineffective. The need for new antimicrobial agents is a well‐documented issue relating to world health. Tremendous efforts have been given to developing compounds that not only show high efficacy, but also those that are less susceptible to resistance development in the bacteria. However, the development of newer, stronger antibiotics which can overcome these acquired resistances is still a scientific challenge because a new mode of antimicrobial action is likely required. To that end, amphiphilic, cationic polymers have emerged as a promising candidate for further development as an antimicrobial agent with decreased potential for resistance development. These polymers are designed to mimic naturally occurring host‐defense antimicrobial peptides which act on bacterial cell walls or membranes. Antimicrobial‐peptide mimetic polymers display antibacterial activity against a broad spectrum of bacteria including drug‐resistant strains and are less susceptible to resistance development in bacteria. These polymers also showed selective activity to bacteria over mammalian cells. Antimicrobial polymers provide a new molecular framework for chemical modification and adaptation to tune their biological functions. The peptide‐mimetic design of antimicrobial polymers will be versatile, generating a new generation of antibiotics toward implementation of polymers in biomedical applications. WIREs Nanomed Nanobiotechnol 2013, 5:49–66. doi: 10.1002/wnan.1199 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Peptide-Based Structures

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α‐Helical cationic antimicrobial peptide (AMP) and antimicrobial mechanism. (a) α‐helical structure of magainin‐2 (pdbID: 2MAG). Cationic residues are colored blue while hydrophobic residues are green. (b) Representation of the selectivity of AMPs to bacteria over mammalian cells based on coulombic attraction. Anioinc lipid head groups are shaded red, zwitterionic lipid head groups gray, and the peptide color scheme is the same as (a). (c) Proposed membrane‐permeabilization models. (Reprinted with permission from Ref 15. Copyright 2005 Nature Publication Group)

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Self‐degrading copolymers. A polyester‐based antimicrobial copolymer degraded into oligomers by self‐degradation mechanism associated with amidation of ester linkages by primary ammonium side chains. (Reprinted with permission from Ref 43. Copyright 2012 American Chemical Society)

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Antimicrobial random and block copolymers. (a) Cationic amphiphilic block and random vinyl ether copolymers. (b) Biocidal activity of copolymers. BC99.9 (biocidal concentration of polymers for 99.9% killing) is plotted as a function of MPIBVE (mol. % of IBVE units). (c) Hemolytic activity of block and random copolymers with ∼25 mol. % of hydrophobic isobutyl vinyl ether (IBVE) units. (Reprinted with permission from Ref 40. Copyright 2012 American Chemical Society)

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Effect of physiological salts on the antibacterial activity of methacrylate copolymers (PB27: 27% of butyl side chains, PM63: 63% of methyl side chains) and melittin against Escherichia coli (a) and Staphylococcus aureus (b). (Reprinted with permission from Ref 49. Copyright 2011 MDPI)

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pH effect on antimicrobial activity (MIC) of methacrylate copolymers with primary or tertiary ammonium side chains. (Reprinted with permission from Ref 44. Copyright 2009 American Chemical Society)

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Susceptibility of methacrylate copolymers and antibiotics to the development of resistance in Escherichia coli. The polymers are PB27(R = butyl, 27 mol. %) and PM63 (R = methyl, 63 mol. %). (Reprinted with permission from Ref 49. Copyright 2011 MDPI)

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All‐or‐none osmotic hemolysis induced by methacrylate polymer. The polymer PB27 contains 27 mol. % of butyl groups. (a) The correlation between percentages of hemolysis (released hemoglobin) and disappeared cells. The good correlation suggests that the hemolysis caused by the polymer is an all‐or‐none type event. (b) Schematic presentation of all‐or‐none and graded release of hemoglobin from RBCs. (c) Osmotic protection by polyethylene glycols (PEGs). High molecular weight (MW) PEGs (> 1000) suppressed hemolysis by the polymer. The threshold MW of PEG for hemolysis inhibition is 500–1000, corresponding to 1.6–2 nm in diameter. (d) Schematic representation of the osmotic lysis mechanism of polymer action. (Reprinted with permission from Ref 48. Copyright 2011 American Chemical Society)

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Hemolytic activity of methacrylate copolymers. (a) Molecular weight (MW) dependence of hemolytic activity. High MW copolymers are more hemolytic. (b) Correlation between the number of hydrophobic groups in a polymer chain and HC50. (Reprinted with permission from Ref 50. Copyright 2009 Wiley‐VCH Verlag GmbH & Co. KGaA)

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Killing kinetics. The polymers are PB27 (R = butyl, 27 mol. %) and PM63 (R = methyl, 63 mol. %). The copolymers are tested at two times minimum inhibitory concentration (MIC) against Staphylococcus aureus sub‐cultured from the exponential (red closed markers and solid lines) or stationary (blue open markers and dashed lines) phase of S. aureus. The MICs of PB27 and PM63 are 16 µg/mL and 250 µg/mL, respectively. (Reprinted with permission from Ref 49. Copyright 2011 MDPI)

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Methacrylate copolymers with different chemical structures of ammonium groups. The mole percentage of methyl groups is 47–48%. (a) Antimicrobial activity and (b) effect of amine groups on polymer partition between octanol and aqueous buffer (pH 6) in the presence of phospholipid‐mimic surfactant (Dodecylphosphate). Partition coefficient P is defined as P = [Polymer]in octanol/[Polymer]in buffer. (Reprinted with permission (a) from Ref 44. Copyright 2009 American Chemical Society; (b) from Ref 45. Copyright 2011 American Chemical Society)

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Simulated binding and insertion of methacrylate copolymers into lipid bilayers. (a) Model polymer structures with different cationic spacer arm lengths, m = 2 (E2), 4 (E4), and 6 (E6). (b) Snapshots of polymers inserted into phosphatidylethanolamine/ palmitoyloleoylphosphatidyl glycerol (POPE/POPG) lipid bilayers. (c) Conformation of E4 in the lipid bilayer. The polymer structures are presented by green (polymer backbone), red (cationic side chains), and blue (hydrophobic ethyl side chains) colors. (Reprinted with permission from Ref 47. Copyright 2012 American Chemical Society)

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Several examples of antimicrobial peptide (AMP)‐mimicking polymers based on (a) methacrylate,37 (b) norbornene,38 (c) nylon,39 (d) vinyl ether,40 and (e) alternating ring‐opening metathesis polymerization (ROMP) copolymers41.

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