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. 2015 Dec 14;16(12):3845-52.
doi: 10.1021/acs.biomac.5b01162. Epub 2015 Nov 19.

Antimicrobial Peptide Mimicking Primary Amine and Guanidine Containing Methacrylamide Copolymers Prepared by Raft Polymerization

Sarah E Exley  1   2 , Lea C Paslay  1   2 , Gyan S Sahukhal  1   2 , Brooks A Abel  1   2 , Tyler D Brown  1   2 , Charles L McCormick  1   2 , Sabine Heinhorst  1   2 , Veena Koul  1   2 , Veena Choudhary  1   2 , Mohamed O Elasri  1   2 , Sarah E Morgan  1   2
Affiliations

Antimicrobial Peptide Mimicking Primary Amine and Guanidine Containing Methacrylamide Copolymers Prepared by Raft Polymerization

Sarah E Exley et al. Biomacromolecules. .

Abstract

Naturally occurring antimicrobial peptides (AMPs) display the ability to eliminate a wide variety of bacteria, without toxicity to the host eukaryotic cells. Synthetic polymers containing moieties mimicking lysine and arginine components found in AMPs have been reported to show effectiveness against specific bacteria, with the mechanism of activity purported to depend on the nature of the amino acid mimic. In an attempt to incorporate the antimicrobial activity of both amino acids into a single water-soluble copolymer, a series of copolymers containing lysine mimicking aminopropyl methacrylamide (APMA) and arginine mimicking guanadinopropyl methacrylamide (GPMA) were prepared via aqueous RAFT polymerization. Copolymers were prepared with varying ratios of the comonomers, with degree of polymerization of 35-40 and narrow molecular weight distribution to simulate naturally occurring AMPs. Antimicrobial activity was determined against Gram-negative and Gram-positive bacteria under conditions with varying salt concentration. Toxicity to mammalian cells was assessed by hemolysis of red blood cells and MTT assays of MCF-7 cells. Antimicrobial activity was observed for APMA homopolymer and copolymers with low concentrations of GPMA against all bacteria tested, with low toxicity toward mammalian cells.

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Figures

Figure 1
Figure 1
Kinetic plots for the polymerization of 1:1 molar ratio of APMA:GPMA: (a) ln([M]0/[M]) as a function of time, (b) SEC overlay at specified reaction times, (c) MWD vs % conversion, and (d) theoretical and experimental Mn vs % conversion.
Figure 2
Figure 2
Hemolysis testing, where percent hemolysis of red blood cells as a function of relevant antimicrobial concentrations is shown for all synthesized AMP mimics.
Scheme 1
Scheme 1
Synthesis of BOC-Protected GPMA
Scheme 2
Scheme 2
Deprotection of BOC-Protected GPMA
Scheme 3
Scheme 3
Aqueous RAFT Polymerization of Poly(APMA-stat-GPMA)
See this image and copyright information in PMC

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