Long‐subchain hyperbranched poly(aminoethyl acrylate): A potent antimicrobial polymer with low hemolytic toxicity

The emergency of antibiotic‐resistant bacteria and their wide spread has posed a worldwide threat to public health, and traditional antibiotics are gradually overwhelmed by infectious bacteria. Herein, we report an efficient and economical strategy to construct antimicrobial polymers with net cationic component and hyperbranched architecture, which exhibit highly selective toxicity toward bacteria over human cells. To this aim, cationic poly(aminoethyl acrylate) (PAEA) without hydrophobicity is chosen for low hemolysis activity and targeting the negative bacterial membranes, and hyperbranched architecture is introduced to solve the dilemma of low antimicrobial activity. Long‐subchain hyperbranched PAEA (lhb‐PAEA) samples kills >99.99% gram‐negative Escherichia coli and >98% gram‐positive Staphylococcu aureus at the dose of ≤4 μg/mL. Moreover, lhb‐PAEA samples exhibit great biocompatibility, for the hemolysis percentage was ≤35% even at the high dose of 1024 μg/mL. Thus, enhanced antimicrobial activity, reduced hemolytic toxicity, the feasible and low‐cost production are achieved for lhb‐PAEA as antimicrobial agents. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3462–3469     

Deformylated Gramicidin A and Its Derivatives Showing High Antimicrobial Activity and Low Hemolytic Toxicity

Gramicidin A is a natural peptide, which shows high antimicrobial activity to Gram‐positive bacteria. However, the hemolytic toxicity prevents its therapeutic usage. We demonstrated that by simply removing the formyl group at the N terminus, the hemolytic toxicity of the peptide could be obviously decreased. The deformylated gramicidin A ( 1 ) could efficiently insert into the lipid bilayer to form transmembrane channels. The peptide can also selectively insert into the membrane of Gram‐positive bacteria but not that of erythrocytes, leading to its high antimicrobial activity and very low hemolytic toxicity. The derivation of 1 could be achieved by decoration at the terminal NH₂ group, which also produced peptides showing high activity and low hemolytic toxicity. This derivation method provided us with an efficient strategy to build a library for future activity and cytotoxicity screening in vitro and in vivo.     

Gel forming waterborne dispersion polymerization of sodium p‐styrene sulfonate with glycidyl methacrylate

Water soluble monomer like sodium p‐styrene sulfonate (SSS) is copolymerized with hydrophobic and reactive monomer glycidyl methacrylate (GMA). The polymerization proceeds as dispersion and forms gels. The gel forming nature prevails even with other hydrophobic and hydrophilic monomers to form ternary polymeric systems. The swelling is dependent on polymer composition as well as the treatment history of polymers. SSS also induces ring opening of GMA to form 1,2‐diols as confirmed independently by various model reactions. The ability of hydrogels to absorb various dyes indicates that owing to the anionic nature, hydrogels absorb cationic dyes nearly quantitatively. Because of their strong affinity to cationic species these hydrogel forming polymers are potentially useful in water purification applications as well as purification of proteins. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 626–634     

Fast fabrication of superabsorbent polyampholytic nanocomposite hydrogels via plasma‐ignited frontal polymerization

We report the facile synthesis of poly(VI‐co‐MAA) superabsorbent polyampholytic hydrogels (VI = N‐vinylimidazole, MAA = methacrylic acid) via plasma‐ignited frontal polymerization (PIFP). On igniting the top surface of the reactants with air plasma, frontal polymerization occurred and poly(VI‐co‐MAA) hydrogels were obtained within minutes. The preparation parameters were investigated, along with swelling capacity, morphology, and chemical structures of poly(VI‐co‐MAA) hydrogels. Interestingly, the hydrogels are superabsorbent in water and show ampholytic characteristic toward pH. Moreover, the hydrogels are able to capture cationic dyes through electrostatic interaction, offering the potential for further development as dye adsorbents for water purification. In addition, nanocomposite hydrogels were obtained by embedding quantum dots (carbon dots or CdS nanocrystals) into the polymer matrix, which endows the nanocomposite hydrogels with favorable fluorescence and potential applications in bioimaging and biosensing. The results indicate that FP can be applied as an alternative means for facile synthesis of multifunctional hydrogels with additional efficiency and energy‐saving. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 912–920     

Di‐N‐Methylation of Anti‐Gram‐Positive Aminoglycoside‐Derived Membrane Disruptors Improves Antimicrobial Potency and Broadens Spectrum to Gram‐Negative Bacteria

The effect of di‐N‐methylation of bacterial membrane disruptors derived from aminoglycosides (AGs) on antimicrobial activity is reported. Di‐N‐methylation of cationic amphiphiles derived from several diversely structured AGs resulted in a significant increase in hydrophobicity compared to the parent compounds that improved their interactions with membrane lipids. The modification led to an enhancement in antibacterial activity and a broader antimicrobial spectrum. While the parent compounds were either modestly active or inactive against Gram‐negative pathogens, the corresponding di‐N‐methylated compounds were potent against the tested Gram‐negative as well as Gram‐positive bacterial strains. The reported modification offers a robust strategy for the development of broad‐spectrum membrane‐disrupting antibiotics for topical use.     

Poly(2‐oxazoline) hydrogels crosslinked with aliphatic bis(2‐oxazoline)s: Properties,cytotoxicity, and cell cultivation

A series of hydrogels from 2‐ethyl‐2‐oxazoline and three bis(2‐oxazoline) crosslinkers—1,4‐butylene‐2,2′‐bis(2‐oxazoline), 1,6‐hexamethylene‐2,2′‐bis(2‐oxazoline), and 1,8‐octamethylene‐2,2′‐bis(2‐oxazoline)—are prepared. The hydrogels differ by the length of aliphatic chain of crosslinker and by the percentage of crosslinker (2–10%). The influence of the type and the percentage of the crosslinker on swelling properties, mechanical properties, and state of water is studied. The equilibrium swelling degree in water ranges from 2 to 20. With a proper selection of the crosslinker, Young's modulus can be varied from 10 kPa to almost 100 kPa. To evaluate the potential for medical applications, the cytotoxicity of extracts and the contact toxicity toward murine fibroblasts are measured. The hydrogels with the crosslinker containing a shorter aliphatic exhibit low toxicity toward fibroblast cells. Moreover, the viability and the proliferation of pancreatic β‐cells incubated inside hydrogels for 12 days are analyzed. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1548–1559     

New,strong cationic hydrogels: Preparation of N,N,N′,N′‐tetraallyl piperazinium dibromide and its copolymers with N,N‐diallyl morpholinium bromide

N,N,N′,N′‐tetraallyl piperazinium dibromide (TAP) has been prepared in high yields by quaternization of N,N′‐diallyl piperazine with allyl bromide. Herein, we have described preparation of nonhydrolysable, strong, cationic hydrogels by copolymerization of TAP with N,N‐diallyl morpholinium bromide (DAM) in the presence of t‐butyl hydroperoxide as initiator in aqueous solutions. Because the monomer and crosslinker involved consist of quaternary amine functions, these hydrogels are fully cationic and do not carry hydrolysable groups. Contrary to expectations, the quaternary amine hydrogels presented do not show any super absorbency, instead dry gel particles in water undergo spontaneous disintegration with an audible bursting of the particles due to instantaneous, high osmotic pressure. Whereas, in KBr or HBr solutions, the swellings are relatively slow. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1006–1013, 2000     

Surface antimicrobial modification of polyamide by poly(hexamethylene guanidine) hydrochloride

Antimicrobial polyamide (PA) received much attention for the demand of packaging and biomedical fields. In this paper, an antimicrobial PA6 membrane was prepared via a surface chemical reaction. A highly effective antibacterial component (PHMG‐E) with terminal epoxy group was firstly synthesized via a reaction between polyhexamethylene guanidine hydrochloride (PHMG) and ethylene glycol diglycidyl ether (EGDE). Then, PHMG‐E was bonded on the surface of PA6 membrane with secondary amine reduced by borane‐tetrahydrofuran (BH₃‐THF). The antimicrobial rates of surface‐modified PA6 membrane (PA6‐PHMG) against Escherichia coli and Staphylococcus aureus were both higher than 99.99%, and the PHMG was non‐leaching due to the chemical bonding. The hydrophilicity of antibacterial PA6 membrane was also significantly improved and the mechanical performance became better.     

Contact Active Antimicrobial Coatings Prepared by Polymer Blending

Herein, contact active antimicrobial films are prepared by simply blending cationic amphiphilic block copolymers with commercial polystyrene (PS). The copolymers are prepared by combining atom transfer radical polymerization and “click chemistry.” A variety of copolymers are synthesized, and composed of a PS segment and an antimicrobial block bearing flexible side chain with thiazole and triazole groups, 4‐(1‐(2‐(4‐methylthiazol‐5‐yl)ethyl)‐1H‐1,2,3‐triazol‐4‐yl) butyl methacrylate (TTBM). The length of the TTBM block is varied as well as the alkylating agent. Different films are prepared from N,N‐dimethylformamide solution, containing variable PS‐b‐PTTBM/PS ratio: from 0 to 100 wt%. Remarkably, the blend films, especially those with 30 and 50 wt% of copolymers, exhibit excellent antimicrobial activities against Gram‐positive, Gram‐negative bacteria and fungi, even higher than films prepared exclusively from the cationic copolymers. Blends composed of 50 wt% of the copolymers present a more than 99.999% killing efficiency against the studied microorganisms. The better activity found in blends can be due to the higher roughness, which increases the surface area and consequently the contact with the microorganisms. These results demonstrate that the use of blends implies a reduction of the content of antimicrobial agent and also enhances the antimicrobial activity, providing new insights for the better designing of antimicrobial coatings.     

Antimicrobial Photodynamic Efficiency of Novel Cationic Porphyrins towards Periodontal Gram‐positive and Gram‐negative Pathogenic Bacteria

The Gram‐negative Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum are major causative agents of aggressive periodontal disease. Due to increase in the number of antibiotic‐resistant bacteria, antimicrobial Photodynamic therapy (aPDT) seems to be a plausible alternative. In this work, photosensitization was performed on Gram‐positive and Gram‐negative bacteria in pure culture using new‐age cationic porphyrins, namely mesoimidazolium‐substituted porphyrin derivative ( ImP ) and pyridinium‐substituted porphyrin derivative ( PyP ). The photophysical properties of both the sensitizers including absorption, fluorescence emission, quantum yields of the triplet excited states and singlet oxygen generation efficiencies were evaluated in the context of aPDT application. The studied porphyrins exhibited high ability to accumulate into bacterial cells with complete penetration into early stage biofilms. As compared with ImP, PyP was found to be more effective for photoinactivation of bacterial strains associated with periodontitis, without any signs of dark toxicity, owing to its high photocytotoxicity.     

Oxidative Cyclization of Isoniazid with Fluoroquinolones: Synthesis,Antibacterial and Antitubercular Activity of New 2,5‐disubstituted‐1,3,4‐Oxadiazoles

We report herein one‐pot synthesis and the antibacterial and antitubercular activities of 2,5‐disubstituted‐1,3,4‐oxadiazole compounds obtained by hybridization of a well‐known antitubercular agent isoniazid (INH ) with four broad‐spectrum antibiotics belonging to fluoroquinolone (FQ ) class. The work is aimed at designing and developing potential antimicrobial agents having synergistic action due to the coupling of INH and FQ through the biologically active 1,3,4‐oxadiazole nucleus. The synthesized compounds are expected to have low toxicity as compared to INH due to the absence of free hydrazide group in the chemical structure of the prepared derivatives. The antibacterial activities of the 1,3,4 oxadiazole derivatives were also tested against several Gram‐positive and Gram‐negative pathogenic bacterial strains. The antitubercular activity was evaluated against M. tuberculosis H₃₇Rv strain, and the results were compared with that of the positive control INH . The title compounds showed excellent antimicrobial and promising antitubercular activity in comparison to the parent fluoroquinolones and INH , respectively.     

Temperature‐responsive linear polyelectrolytes and hydrogels based on [2‐(methacryloyloxy)ethyl] trimethylammonium chloride and N‐isopropylacrylamide and their complex formation with potassium hexacyanoferrates (II,III)

Water‐soluble temperature‐responsive polyelectrolytes and hydrogels have been synthesized by γ‐radiation copolymerization of [2‐(methacryloyloxy)‐ethyl]trimethylammonium chloride with N‐isopropylacrylamide. Complex formation of soluble copolymers with potassium hexacyanoferrates (II, III) was studied in aqueous solutions. It was shown that, depending on the concentration and temperature, the formation of soluble or insoluble polycomplexes is observed. The hydrogels show good ability to absorb potassium hexacyanoferrates (II, III) from aqueous solutions. Sorption ability of hydrogels depends on the content of cationic monomer in copolymer and the nature of coordination ion. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 515–522, 2004     

Developments in antimicrobial polymers

Effective antimicrobial polymers have been attracting more interests because of the low propensity to cause drug-resistant microorganisms. The recent progresses in antimicrobial polymers are updated according to the action approaches, that is, antimicrobial polymers with free mobility or fixed on surfaces, respectively. Free antimicrobial polymers kill pathogens majorly via electrostatic interaction followed by disruption of the cell membranes; strong antimicrobial activity of primary/secondary amines, new chemical units, and peptides without facial amphiphilicity are highlighted; and the dependences on amphiphilicity, topology, and self-assembly profiles are summarized. Antimicrobial polymers fixed on surfaces kill pathogens via interaction with the cell membranes of pathogens via electrostatic or hydrophobic interaction; approaches to antimicrobial surfaces based on covalently grafting, anchoring, and bulk-mixing of polymers are summarized; and new designs of sustainable antimicrobial surfaces and hydrogels are highlighted. Deep biology understanding and development strategies of materials are suggested for the future. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 632–639     

Swelling behavior of poly{N‐[3‐(dimethylaminopropyl)] methacrylamide‐co‐acrylamide} hydrogels in aqueous solutions of surfactants

Temperature sensitive poly{N‐[3‐(dimethylaminopropyl)]methacrylamide‐co‐acrylamide} [P(DMAPMA‐co‐AAm)] hydrogels were prepared by the free‐radical crosslinking copolymerization of corresponding monomers in water with N,N‐methylenebisacrylamide as the crosslinker, ammonium persulfate as the initiator, and N,N,N′,N′‐tetramethylethylenediamine as the activator. The swelling equilibrium of the P(DMAPMA‐co‐AAm) hydrogels was investigated as a function of temperature in aqueous solutions of the anionic surfactant sodium dodecyl sulfate and the cationic surfactant dodecyltrimethylammonium bromide. In pure water, regardless of the amount of N,N‐methylenebisacrylamide, the P(DMAPMA‐co‐AAm) hydrogels showed a discontinuous phase transition between 30 and 36 °C. However, the transition temperature changed from discontinuous to continuous with the addition of surfactants; this was ascribed to the conversion of nonionic P(DMAPMA‐co‐AAm) hydrogels into polyelectrolyte hydrogels due to the binding of surfactants through hydrophobic interactions. Additionally, the concentrations of free sodium dodecyl sulfate and dodecyltrimethylammonium bromide ions were measured at different temperatures by conductometry, and it was found that the electric conductivity of the P(DMAPMA‐co‐AAm)–surfactant systems depended strongly on the swelling ratio; most notably, it changed drastically near the phase‐transition temperature of the P(DMAPMA‐co‐AAm) hydrogel. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 1645–1652, 2006     

Radical‐medicated end‐group transformation of amphiphilic methacrylate random copolymers for modulation of antimicrobial and hemolytic activities

This work describes synthesis of antimicrobial methacrylate copolymers by reversible addition‐fragmentation chain transfer (RAFT) polymerization and examines the versatility of this approach for improving chemical optimization to create potent, non‐toxic antimicrobial polymers. Specifically, this study focuses on the radical‐mediated transformation of end group of antimicrobial peptide‐mimetic polymer. RAFT polymerization using 2‐cyano‐2‐yl‐dithiobenzoate provided a statistical methacrylate copolymer consisting of aminobutyl and ethyl groups in the side chains. The following radical‐mediated modification using free radical initiators successfully transformed the ω‐end group of parent copolymer from dithiobenzoate to a cyanoisobutyl or aminoethyl cyanopentanoate group without any significant changes to the polymer molecular weight. In general, the parent polymer and variants showed a broad spectrum of activity against a panel of bacteria, but low hemolytic activity against human red blood cells. The parent copolymer with the dithiobenzoate end‐group showed highest antimicrobial and hemolytic activities as compared with other copolymers. The copolymers caused membrane depolarization in Staphylococcus aureus, while the ability of copolymers for membrane disruption is not dependent on the end‐group structures. The synthetic route reported in this study will be useful for further study of the role of polymer end‐groups in the antimicrobial activity of copolymers. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 304–312     

Nanocomposite hydrogel consisting of Na‐montmorillonite with enhanced mechanical properties

A new kind of nanocomposite (NC) hydrogel with Na‐montmorillonite (MMT) is presented in this article. The NC hydrogels were synthesized by free radical copolymerization of acrylamide and (3‐acrylamidopropyl) trimethylammonium chloride (ATC) in the presence of MMT and N,N′‐methylene‐bis‐acrylamide used as chemical cross‐linker. Due to the cation‐exchange reaction between MMT and ATC (cationic monomer) during the synthesis of NC hydrogels, MMT platelets were considered chemical “plane” cross‐linkers, different from “point” cross‐linkers. With increasing amount of MMT, the crosslinking degree enhanced, causing a decrease of the swelling degree at equilibrium. Investigations of mechanical properties indicated that NC hydrogels exhibited enhanced strength and toughness, which resulted from chemical interaction between exfoliated MMT platelets and polymer chains in hydrogels. Dynamic shear measurements showed that both storage modulus and loss modulus increased with increasing MMT content. The idea described here provided a new route to prepare hydrogels with high mechanical properties by using alternative natural Na‐MMT. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 1020–1026     

Antimicrobial polymers containing melamine derivatives. II. Biocidal polymers derived from 2‐vinyl‐4,6‐diamino‐1,3,5‐triazine

Poly(2‐vinyl‐4,6‐diamino‐1,3,5‐triazine) (PVDAT) and a series of poly(styrene‐co‐2‐vinyl‐4,6‐diamino‐1,3,5‐triazine) (PS‐co‐VDAT) copolymers were synthesized via conventional free‐radical polymerizations. The polymer structures were confirmed by Fourier transform infrared, NMR, and elemental analysis. The molecular weights were determined by gel permeation chromatography studies, and the thermal properties were characterized by differential scanning calorimetry and thermogravimetric analysis. After treatment with chlorine bleach, PVDAT and PS‐co‐VDAT provided potent antimicrobial functions against multidrug‐resistant Gram‐negative and Gram‐positive bacteria. The antimicrobial functions were durable for longer than 3 months and rechargeable for more than 50 times. The structure–property relationship of the polymers was further discussed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4089–4098, 2005     

An Adamantyl Amino Acid Containing Gramicidin S Analogue with Broad Spectrum Antibacterial Activity and Reduced Hemolytic Activity

The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram‐negative and Gram‐positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic.     

Polyelectrolyte multilayers prepared on hydrogel surfaces

Poly(vinyl alcohol) hydrogels were alternately immersed in aqueous solutions of oppositely charged polymers. The adsorption of the cationic dye methylene blue to the immersed hydrogels suggested the presence of a coating on the hydrogel surfaces. Static contact angles with an air bubble in water showed layer‐by‐layer growth of the films. The films could be transferred onto solid substrates for mechanical strength after the hydrogels were placed on the solid substrates, and this resulted in an estimation of the film thickness. The number of assembly steps could regulate the film thickness. We present here coatings of hydrogels with thin polymer films prepared by layer‐by‐layer assembly. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 1062–1067, 2005     

Fluorescence resonance energy transfer by quencher adsorption into hydrogels containing fluorophores

We synthesized anionic hydrogels containing fluorophores and investigated the adsorption of a cationic quencher having an amino group into hydrogels by fluorescence resonance energy transfer (FRET). FRET from the fluorophore to the quencher in hydrogels was examined by fluorescence intensity and fluorescence decay using a fluorescence spectrophotometer and femtosecond laser spectroscopy. The fluorescence intensity of the fluorophore‐containing hydrogels decreased rapidly with increasing amounts of adsorbed cationic quencher. The fluorescence emission of the fluorophore in the quencher‐adsorbed hydrogels containing fluorophores decayed more rapidly than that of the original hydrogels. The aforementioned result indicates that the fluorescence of the fluorophore‐containing hydrogels is quenched due to FRET from the fluorophore to the quencher as the cationic quenchers can approach the fluorophores in hydrogels by electrostatic interactions. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 3245–3252, 2006