@article {723, title = {New bactericidal surgical suture coating.}, journal = {Langmuir}, volume = {28}, year = {2012}, month = {2012 Aug 21}, pages = {12134-9}, abstract = {This paper demonstrates the effectiveness of a new antimicrobial suture coating. An amphiphilic polymer, poly[(aminoethyl methacrylate)-co-(butyl methacrylate)] (PAMBM), inspired by antimicrobial peptides, was bactericidal against S. aureus in time-kill experiments. PAMBM was then evaluated in a variety of polymer blends using the Japanese Industrial Standard (JIS) method and showed excellent antimicrobial activity at a low concentration (0.5 wt \%). Using a similar antimicrobial coating formula to commercial Vicryl Plus sutures, disk samples of the coating material containing PAMBM effectively killed bacteria (98\% reduction at 0.75 wt \%). Triclosan, the active ingredient in Vicryl Plus coatings, did not kill the bacteria. Further Kirby-Bauer assays of these disk samples showed an increasing zone of inhibition with increasing concentration of PAMBM. Finally, the PAMBM-containing coating was applied to sutures, and the morphology of the coating surface was characterized by SEM, along with Vicryl and uncoated sutures. The PAMBM-containing sutures killed bacteria more effectively (3 log(10) reduction at 2.4 wt \%) than Vicryl Plus sutures (0.5 log(10) reduction).}, issn = {1520-5827}, doi = {10.1021/la302732w}, author = {Li, Yan and Kumar, Kushi N and Dabkowski, Jeffrey M and Corrigan, Meagan and Scott, Richard W and N{\"u}sslein, Klaus and Tew, Gregory N} } @article {733, title = {Antimicrobial polymers prepared by ring-opening metathesis polymerization: manipulating antimicrobial properties by organic counterion and charge density variation.}, journal = {Chemistry}, volume = {15}, year = {2009}, month = {2009 Nov 2}, pages = {11715-22}, abstract = {The synthesis and characterization of a series of poly(oxanorbornene)-based synthetic mimics of antimicrobial peptides (SMAMPs) is presented. In the first part, the effect of different organic counterions on the antimicrobial properties of the SMAMPs was investigated. Unexpectedly, adding hydrophobicity by complete anion exchange did not increase the SMAMPs{\textquoteright} antimicrobial activity. It was found by dye-leakage studies that this was due to the loss of membrane activity of these polymers caused by the formation of tight ion pairs between the organic counterions and the polymer backbone. In the second part, the effect of molecular charge density on the biological properties of a SMAMP was investigated. The results suggest that, above a certain charge threshold, neither minimum inhibitory concentration (MIC90) nor hemolytic activity (HC50) is greatly affected by adding more cationic groups to the molecule. A SMAMP with an MIC90 of 4 microg mL(-1) against Staphylococcus aureus and a selectivity (=HC50/MIC90) of 650 was discovered, the most selective SMAMP to date.}, keywords = {Anti-Infective Agents, Biomimetic Materials, Cations, Diamines, Hemolysis, Hydrophobic and Hydrophilic Interactions, Microbial Sensitivity Tests, Polymers}, issn = {1521-3765}, doi = {10.1002/chem.200900606}, author = {Lienkamp, Karen and Madkour, Ahmad E and Kumar, Kushi-Nidhi and N{\"u}sslein, Klaus and Tew, Gregory N} } @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 {734, title = {"Doubly selective" antimicrobial polymers: how do they differentiate between bacteria?}, journal = {Chemistry}, volume = {15}, year = {2009}, month = {2009 Nov 2}, pages = {11710-4}, abstract = {We have investigated how doubly selective synthetic mimics of antimicrobial peptides (SMAMPs), which can differentiate not only between bacteria and mammalian cells, but also between Gram-negative and Gram-positive bacteria, make the latter distinction. By dye-leakage experiments on model vesicles and complementary experiments on bacteria, we were able to relate the Gram selectivity to structural differences of these bacteria types. We showed that the double membrane of E. coli rather than the difference in lipid composition between E. coli and S. aureus was responsible for Gram selectivity. The molecular-weight-dependent antimicrobial activity of the SMAMPs was shown to be a sieving effect: while the 3000 g mol(-1) SMAMP was able to penetrate the peptidoglycan layer of the Gram-positive S. aureus bacteria, the 50000 g mol(-1) SMAMP got stuck and consequently did not have antimicrobial activity.}, keywords = {Anti-Infective Agents, Biomimetic Materials, Escherichia coli, Microbial Sensitivity Tests, Peptidoglycan, Polymers, Staphylococcus aureus}, issn = {1521-3765}, doi = {10.1002/chem.200802558}, author = {Lienkamp, Karen and Kumar, Kushi-Nidhi and Som, Abhigyan and N{\"u}sslein, Klaus and Tew, Gregory N} } @article {737, title = {Fast disinfecting antimicrobial surfaces.}, journal = {Langmuir}, volume = {25}, year = {2009}, month = {2009 Jan 20}, pages = {1060-7}, abstract = {Silicon wafers and glass surfaces were functionalized with facially amphiphilic antimicrobial copolymers using the "grafting from" technique. Surface-initiated atom transfer radical polymerization (ATRP) was used to grow poly(butylmethacrylate)-co-poly(Boc-aminoethyl methacrylate) from the surfaces. Upon Boc-deprotection, these surfaces became highly antimicrobial and killed S. aureus and E. coli 100\% in less than 5 min. The molecular weight and grafting density of the polymer were controlled by varying the polymerization time and initiator surface density. Antimicrobial studies showed that the killing efficiency of these surfaces was independent of polymer layer thickness or grafting density within the range of surfaces studied.}, keywords = {Anti-Bacterial Agents, Escherichia coli, Glass, Microbial Sensitivity Tests, Molecular Structure, Particle Size, Polymethacrylic Acids, Silicon, Staphylococcus aureus, Surface Properties}, issn = {0743-7463}, doi = {10.1021/la802953v}, author = {Madkour, Ahmad E and Dabkowski, Jeffery M and Nusslein, 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} } @article {747, title = {Broad-spectrum antibacterial activity by a novel abiogenic peptide mimic.}, journal = {Microbiology}, volume = {152}, year = {2006}, month = {2006 Jul}, pages = {1913-8}, abstract = {The human-mediated use and abuse of classical antibiotics has created a strong selective pressure for the rapid evolution of antibiotic resistance. As resistance levels rise, and the efficacy of classical antibiotics wanes, the intensity of the search for alternative antimicrobials has increased. One class of molecules that has attracted much attention is the antimicrobial peptides (AMPs). They exhibit broad-spectrum activity, they are potent and they are widespread as part of the innate defence system of both vertebrates and invertebrates. However, peptides are complex molecules that suffer from proteolytic degradation. The ability to capture the essential properties of antimicrobial peptides in simple easy-to-prepare molecules that are abiotic in origin and non-proteolytic offers many advantages. Mechanistic and structural knowledge of existing AMPs was used to design a novel compound that mimics the biochemical activity of an AMP. This report describes the development and in vitro characterization of a small peptide mimic that exhibited quick-acting and selective antibacterial activity against a broad range of bacteria, including numerous clinically relevant strains, at low MIC values.}, keywords = {Anti-Bacterial Agents, Drug Design, Humans, Microbial Sensitivity Tests, Peptides}, issn = {1350-0872}, doi = {10.1099/mic.0.28812-0}, author = {N{\"u}sslein, Klaus and Arnt, Lachelle and Rennie, Jason and Owens, Cullen and Tew, Gregory N} } @article {750, title = {Simple oligomers as antimicrobial peptide mimics.}, journal = {J Ind Microbiol Biotechnol}, volume = {32}, year = {2005}, month = {2005 Jul}, pages = {296-300}, abstract = {New approaches to antibiotic design are desperately needed. The design of simple oligomers that capture the shape and biological function of natural antimicrobial peptides could prove to be versatile and highly successful. We discuss the use of aromatic backbones to design facially amphiphilic (FA) beta-sheet like structures which are potently antimicrobial. These oligomers capture the physiochemical properties of peptides like the Magainins and Defensins, which fold into specific conformations that are amphiphilic resulting in antimicrobial activity. However, natural peptides are expensive to prepare and difficult to produce on large scale. The design of polymers and oligomers that mimic the complex structures and remarkable biological properties of proteins is an important endeavor and provides attractive alternatives to the difficult synthesis of natural peptides. We therefore have designed a series of FA oligomers that are easy to prepare from inexpensive monomers. They adopt structures very reminiscent of amphiphilic beta-sheets and have significant activity with minimal inhibitory concentrations at 6 h in the low microgram per ml range (muM to nM). They are active against a broad spectrum of bacteria including gram-positive and gram-negative as well as antibiotic resistant strains.}, keywords = {Amides, Anti-Bacterial Agents, Antimicrobial Cationic Peptides, Drug Resistance, Bacterial, Gram-Negative Bacteria, Gram-Positive Bacteria, Inhibitory Concentration 50, Peptides, Protein Conformation}, issn = {1367-5435}, doi = {10.1007/s10295-005-0219-0}, author = {Rennie, Jason and Arnt, Lachelle and Tang, Haizhong and N{\"u}sslein, Klaus and Tew, Gregory N} } @article {752, title = {Tuning the hemolytic and antibacterial activities of amphiphilic polynorbornene derivatives.}, journal = {J Am Chem Soc}, volume = {126}, year = {2004}, month = {2004 Dec 8}, pages = {15870-5}, abstract = {Amphiphilic cationic polynorbornene derivatives, soluble in water, were prepared from modular norbornene monomers, with a wide range of molecular weights (M(n) = 1600-137 500 g/mol) and narrow polydispersities (PDI = 1.1-1.3). The antibacterial activity determined by growth inhibition assays and the hemolytic activity against human red blood cells were measured and compared to determine the selectivity of the polymers for bacterial over mammalian cells. The effects of monomer repeat unit hydrophobicity and polymer molecular weight on antibacterial and hemolytic activities were determined. The hydrophobicity of the repeat unit was observed to have dramatic effects on antibacterial and hemolytic activities. Lipid membrane disruption activities of the polymers was confirmed by measuring polymer-induced dye leakage from large unilamellar vesicles. By tuning the overall hydrophobicity of the polymer through random copolymerizations of modular norbornene derivatives, highly selective, nonhemolytic antibacterial activities were obtained. For appropriate monomer composition, selectivity against bacteria versus human red blood cells was determined to be over 100.}, keywords = {Anti-Bacterial Agents, Bacillus subtilis, Cell Membrane, Cholesterol, Erythrocytes, Escherichia coli, Hemolysis, Humans, Liposomes, Microbial Sensitivity Tests, Molecular Weight, Norbornanes, Polymers, Structure-Activity Relationship}, issn = {0002-7863}, doi = {10.1021/ja045664d}, author = {Ilker, M Firat and N{\"u}sslein, Klaus and Tew, Gregory N and Coughlin, E Bryan} }