Antimicrobial Polymers: Peptide-Mimetic Design and Mechanism of Action.

[摘要] The proliferation of antibiotic-resistant bacteria and the decline in new antibiotic drug approvals have lead to an emergent need for novel antibacterial strategies.In nature, host defense peptides (HDPs) kill invading pathogens as part of the innate immune system in multicelluar organisms.HDPs are diverse in sequence and conformation, but certain physiochemical features are conserved: they are cationic (+1-5 net charge), amphiphilic (30-50% hydrophobic residues), and low molecular weight (10-50 residues).Their putative mechanism involves the disruption of bacterial membranes.Because the activity of these peptides is modulated by physiochemical characteristics, rather than receptor-specific interactions, we hypothesized that synthetic macromolecules could mimic their function.The peptide-mimetic design strategy has several advantages including diminished cost of manufacturing, lower susceptibility to degradation, and access to the wide range of chemical functionalities obtained by synthetic means.Random copolymers composed of ~50% cationic (aminoethylmethacrylate) and ~50% hydrophobic (methyl methacrylate) monomer units, and molecular weights of 1-4 kDa, inhibited bacterial growth at concentrations as low as ~10µM whereas they did not lyse human red blood cells up to ~1000µM.Polymers bearing primary amine groups in the side chains displayed more potent activity than analogous polymers containing quaternary ammonium salts, attributed the higher affinity of primary amines for phosphate lipid head groups, leading to efficient membrane permeabilization. Polymethacrylamides showed low µM antibacterial activity without harming RBCs, although they were cytotoxic to human epithelial cells.After further optimization, copolymers bearing aminobutyl side chains showed highest activity among other polymers bearing shorter (aminoethyl) and longer (aminohexyl) cationic side chains. Biophysical experiments using model lipid membranes, fluorescence imaging, flow cytometry, and molecular dynamics simulations indicated that the mechanism of antimicrobial action involves membrane disruption.Pore formation in cell membranes followed by osmotic lysis and leakage of cytoplasmic contents, results in bacterial cell death.Although synthetic polymers are heterogeneous in structure (polydispersity, random sequence, and heterotacticity) and conformation, they nevertheless effectively mimic the antimicrobial activity and mechanism of host defense peptides.Hence, this emerging class of materials can be excellent candidates for a wide variety of applications in combating the rise of drug-resistant infectious diseases.

[发布机构] University of Michigan

[效力级别] Host Defense Peptide

[关键词] Polymer;Host Defense Peptide;Antimicrobial;Amphiphilic;Membrane Disruption;Mechanism;Chemistry;Microbiology and Immunology;Science;Macromolecular Science & Engineering