@article {739, title = {Comparison of facially amphiphilic versus segregated monomers in the design of antibacterial copolymers.}, journal = {Chemistry}, volume = {15}, year = {2009}, month = {2009}, pages = {433-9}, abstract = {A direct comparison of two strategies for designing antimicrobial polymers is presented. Previously, we published several reports on the use of facially amphiphilic (FA) monomers which led to polynorbornenes with excellent antimicrobial activities and selectivities. Our polymers obtained by copolymerization of structurally similar segregated monomers, in which cationic and non-polar moieties reside on separate repeat units, led to polymers with less pronounced activities. A wide range of polymer amphiphilicities was surveyed by pairing a cationic oxanorbornene with eleven different non-polar monomers and varying the comonomer feed ratios. Their properties were tested using antimicrobial assays and copolymers possessing intermediate hydrophobicities were the most active. Polymer-induced leakage of dye-filled liposomes and microscopy of polymer-treated bacteria support a membrane-based mode of action. From these results there appears to be profound differences in how a polymer made from FA monomers interacts with the phospholipid bilayer compared with copolymers from segregated monomers. We conclude that a well-defined spatial relationship of the whole polymer is crucial to obtain synthetic mimics of antimicrobial peptides (SMAMPs): charged and non-polar moieties need to be balanced locally, for example, at the monomer level, and not just globally. We advocate the use of FA monomers for better control of biological properties. It is expected that this principle will be usefully applied to other backbones such as the polyacrylates, polystyrenes, and non-natural polyamides.}, keywords = {Anti-Bacterial Agents, Bacteria, Cell Membrane, Drug Design, Hemolysis, Plastics, Polymers, Surface-Active Agents}, issn = {1521-3765}, doi = {10.1002/chem.200801233}, author = {Gabriel, Gregory J and Maegerlein, Janet A and Nelson, Christopher F and Dabkowski, Jeffrey M and Eren, Tarik and N{\"u}sslein, Klaus and Tew, Gregory N} } @article {738, title = {Hydrophilic modifications of an amphiphilic polynorbornene and the effects on its hemolytic and antibacterial activity.}, journal = {Biomacromolecules}, volume = {10}, year = {2009}, month = {2009 Feb 9}, pages = {353-9}, abstract = {Here we report the modification of an amphiphilic antibacterial polynorbornene, Poly3, via incorporation of hydrophilic, biocompatible groups. The sugar, zwitterionic, and polyethylene glycol based moieties were incorporated in varying ratios by copolymerization and postpolymerization techniques. Well-defined copolymers with molecular weights of 3 kDa and narrow polydispersity indices ranging from 1.08 to 1.15 were obtained. The effects of these modifications on the biological activity of these polymers were analyzed by determining their minimum inhibitory concentrations (MIC) and their hemolytic activities (HC50).}, keywords = {Anti-Bacterial Agents, Bacteria, Biocompatible Materials, Carbohydrates, Hemolysis, Microbial Sensitivity Tests, Plastics, Polyethylene, Static Electricity}, issn = {1526-4602}, doi = {10.1021/bm801129y}, author = {Colak, Semra and Nelson, Christopher F and N{\"u}sslein, Klaus and Tew, Gregory N} } @article {742, title = {Antimicrobial polymers prepared by ROMP with unprecedented selectivity: a molecular construction kit approach.}, journal = {J Am Chem Soc}, volume = {130}, year = {2008}, month = {2008 Jul 30}, pages = {9836-43}, abstract = {Synthetic Mimics of Antimicrobial Peptides (SMAMPs) imitate natural host-defense peptides, a vital component of the body{\textquoteright}s immune system. This work presents a molecular construction kit that allows the easy and versatile synthesis of a broad variety of facially amphiphilic oxanorbornene-derived monomers. Their ring-opening metathesis polymerization (ROMP) and deprotection provide several series of SMAMPs. Using amphiphilicity, monomer feed ratio, and molecular weight as parameters, polymers with 533 times higher selectivitiy (selecitviy = hemolytic concentration/minimum inhibitory concentration) for bacteria over mammalian cells were discovered. Some of these polymers were 50 times more selective for Gram-positive over Gram-negative bacteria while other polymers surprisingly showed the opposite preference. This kind of "double selectivity" (bacteria over mammalian and one bacterial type over another) is unprecedented in other polymer systems and is attributed to the monomer{\textquoteright}s facial amphiphilicity.}, keywords = {Anti-Infective Agents, Antimicrobial Cationic Peptides, Biomimetic Materials, Erythrocytes, Escherichia coli, Hemolysis, Humans, Hydrophobic and Hydrophilic Interactions, Microbial Sensitivity Tests, Molecular Weight, Norbornanes, Polymers, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Staphylococcus aureus, Structure-Activity Relationship}, issn = {1520-5126}, doi = {10.1021/ja801662y}, author = {Lienkamp, Karen and Madkour, Ahmad E and Musante, Ashlan and Nelson, Christopher F and N{\"u}sslein, Klaus and Tew, Gregory N} } @article {741, title = {Investigating the effect of increasing charge density on the hemolytic activity of synthetic antimicrobial polymers.}, journal = {Biomacromolecules}, volume = {9}, year = {2008}, month = {2008 Oct}, pages = {2805-10}, abstract = {The current study is aimed at investigating the effect of fine-tuning the cationic character of synthetic mimics of antimicrobial peptides (SMAMPs) on the hemolytic and antibacterial activities. A series of novel norbornene monomers that carry one, two, or three Boc-protected amine functionalities was prepared. Ring-opening metathesis polymerization (ROMP) of the monomers, followed by deprotection of the amine groups resulted in cationic antimicrobial polynorbornenes that carry one, two, and three charges per monomer repeat unit. Increasing the number of amine groups on the most hydrophobic polymer reduced its hemolytic activity significantly. To understand the membrane activity of these polymers, we conducted dye leakage experiments on lipid vesicles that mimic bacteria and red blood cell membranes, and these results showed a strong correlation with the hemolysis data.}, keywords = {Amines, Anti-Infective Agents, Antimicrobial Cationic Peptides, Chemistry, Pharmaceutical, Drug Design, Erythrocytes, Escherichia coli, Hemolysis, Humans, Lipids, Magnetic Resonance Spectroscopy, Models, Chemical, Peptides, Polymers, Staphylococcus aureus}, issn = {1526-4602}, doi = {10.1021/bm800569x}, author = {Al-Badri, Zoha M and Som, Abhigyan and Lyon, Sarah and Nelson, Christopher F and N{\"u}sslein, Klaus and Tew, Gregory N} } @article {740, title = {Synthetic mimic of antimicrobial peptide with nonmembrane-disrupting antibacterial properties.}, journal = {Biomacromolecules}, volume = {9}, year = {2008}, month = {2008 Nov}, pages = {2980-3}, abstract = {Polyguanidinium oxanorbornene ( PGON) was synthesized from norbornene monomers via ring-opening metathesis polymerization. This polymer was observed to be strongly antibacterial against Gram-negative and Gram-positive bacteria as well as nonhemolytic against human red blood cells. Time-kill studies indicated that this polymer is lethal and not just bacteriostatic. In sharp contrast to previously reported SMAMPs (synthetic mimics of antimicrobial peptides), PGON did not disrupt membranes in vesicle-dye leakage assays and microscopy experiments. The unique biological properties of PGON, in same ways similar to cell-penetrating peptides, strongly encourage the examination of other novel guanidino containing macromolecules as powerful and selective antimicrobial agents.}, keywords = {Anti-Bacterial Agents, Antimicrobial Cationic Peptides, Erythrocytes, Gram-Negative Bacteria, Gram-Positive Bacteria, Guanidines, Humans, Microbial Sensitivity Tests, Molecular Mimicry, Polymers}, issn = {1526-4602}, doi = {10.1021/bm800855t}, author = {Gabriel, Gregory J and Madkour, Ahmad E and Dabkowski, Jeffrey M and Nelson, Christopher F and N{\"u}sslein, Klaus and Tew, Gregory N} }