Advancements in the Development of Non-Nitrogen-Based Amphiphilic Antiseptics to Overcome Pathogenic Bacterial Resistance

The prevalence of quaternary ammonium compounds (QACs) as common disinfecting agents for the past century has led bacteria to develop resistance to such compounds. Given the alarming increase in resistant strains, new strategies are required to combat this rise in resistance. Recent efforts to probe and combat bacterial resistance have focused on studies of multiQACs. Relatively unexplored, however, have been changes to the primary atom bearing positive charge in these antiseptics. Here we review the current state of the field of both phosphonium and sulfonium amphiphilic antiseptics, both of which hold promise as novel means to address bacterial resistance.     

Efflux Pumps Might Not Be the Major Drivers of QAC Resistance in Methicillin‐Resistant Staphylococcus aureus

Quaternary ammonium compounds (QACs) are commonly used antiseptics that are now known to be subject to bacterial resistance. The prevalence and mechanisms of such resistance, however, remain underexplored. We investigated a variety of QACs, including those with multicationic structures (multiQACs), and the resistance displayed by a variety of Staphylococcus aureus strains with and without genes encoding efflux pumps, the purported main driver of bacterial resistance in MRSA. Through minimum inhibitory concentration (MIC)‐, kinetic‐, and efflux‐based assays, we found that neither the qacR/qacA system present in S. aureus nor another efflux pump system is the main reason for bacterial resistance to QACs. Our findings suggest that membrane composition could be the predominant driver that allows CA‐MRSA to withstand the assault of conventional QAC antiseptics.     

Building a Better Quaternary Ammonium Compound (QAC): Branched Tetracationic Antiseptic Amphiphiles

Bacteria contaminate surfaces in a wide variety of environments, causing severe problems across a number of industries. In a continuation of our campaign to develop novel antibacterial quaternary ammonium compounds (QACs) as useful antiseptics, we have identified a starting material bearing four tertiary amines, enabling the rapid synthesis of several tris‐ and tetracationic QACs. Herein we report the synthesis and biological activity of a series of 24 multiQACs deemed the “superT” family, and an investigation of the role of cationic charge in antimicrobial and anti‐biofilm activity, as well as toxicity. This class represents the most potent series of QACs reported to date against methicillin‐resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MICs) and minimum biofilm eradication concentrations (MBECs) as low as 0.25 and 25 μm , respectively. Based on the significant cell‐surface‐charge differences between bacterial and eukaryotic cells, in certain cases we observed excellent efficacy‐to‐toxicity profiles, exceeding a 100‐fold differential. This work further elucidates the chemical underpinnings of disinfectant efficacy versus toxicity based on cationic charge.     

Charged polyacrylonitrile membranes having amphiphilic quaternized ammonium groups for ultrafiltration

Four types of positively charged polyacrylonitriles having quaternized N,N-dimethylaminoethyl methacrylate (DAMA) were synthesized and were used to prepare ultrafiltration membranes by a phase-inversion method. The effect of aliphatic ethyl, octyl, and stearyl groups and the benzyl group, which covalently bind to the quaternary ammonium group, on filtration properties was studied by ultrafiltration under an applied pressure of 760 mmH₂O. Water permeability through the resultant membranes increased as the aliphatic chain length on the quaternary ammonium group increased. For a copolymer membrane having a benzyl group on the quaternary ammonium group, water permeability was lower than that for the ethyl type of copolymer membrane. The membrane permeability and pore size for the molecular size-exclusion effect were studied at various NaCl concentrations in the 0–0.15M region. The membranes having octyl and stearyl groups showed stable filtration behavior by increase of the NaCl concentration, while the membranes having an ethyl group and a benzyl group on the quaternary ammonium group showed a change of the water permeability due to a pore-size increase for the membrane by NaCl addition. Measurements of membrane potential indicated the shielding of positively charged sites of the membranes by salt addition. Further, the copolymer membranes showed a separation ability for water/2-butanol of low water content. The separation ability was attributed to the chemical structure of the membranes having different interaction characteristics with the mixture components. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 69: 1821–1828, 1998     

Branched Polyvinyl Alcohol Hybrid Membrane for Acid Recovery via Diffusion Dialysis

A branched polymer was prepared by grafting allyltrimethylammonium chloride onto polyvinyl alcohol (PVA) via free‐radical polymerization. Afterwards, a series of hybrid membranes were prepared by sol‐gel cross‐linking between quaternary ammonium‐PVA and tetraethoxysilane. The obtained membranes were characterized in terms of infrared spectroscopy, ion exchange capacity, water uptake, linear expansion ratio, and acid resistance. The thermal properties of the membranes were investigated as well. The diffusion dialysis performances of the membranes were tested by using a simulated feed solution containing HCl and FeCl₂. The diffusion dialysis coefficients and the separation factors were much better than those of the commercial DF‐120 membrane.     

Preparation and antimicrobial activity of Konjac Glucomannan modified with quaternary ammonium compound

Seven kind of graft copolymerization Konjac Glucomannan with quaternary ammonium group have been prepared, using Konjac Glucomannan (KGM) and methacryloxylethyl alkyl dimethyl ammonium bromide with c₈–c₁₈ alkyl and benzyl in water, ceric ammonium nitrate as initiator, the reaction temperature of 348 K, and the reaction period of 3 h. The structures were confirmed by FTIR. The 15 min inhibitory rates of all the graft copolymerization KGM against Escherichia coli and Staphylococcus aureus reached 99.99%, against Candida albicans somewhat lower, but 30 min inhibitory rate still reached 99.02% for graft copolymerization KGM with quaternary ammonium group having 14 alkyl. The antibacterial mechanism of the graft copolymerization KGM has been investigated by adsorption ability to E. coli, measure of 260 nm absorbing materials and SEM micrographs. Firstly, the bacteria were fastly adsorbed by graft copolymerization KGM. Interactions between bacterial membranes and antibacterial product cause fundamental changes in both membrane structure and function, induced leakage of cytoplasmic contents is a classic indication of damage to the bacterial cytoplasmic membrane. The loss of the connection between the outer membrane and the underlying peptidoglycan induces the abnormality of nodular structures and bleb formation of the cell envelope of E. coli. The antibacterial mechanism is in accordance with microbiologic findings identifying surface blebbing as the first morphologic change occurring in the permeability barrier of gram‐negative bacteria under mild heat stress and laser irradiation, etc. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Further Investigations into Rigidity-Activity Relationships in BisQAC Amphiphilic Antiseptics

Thirty-six biscationic quaternary ammonium compounds were efficiently synthesized in one step to examine the effect of molecular geometry of two-carbon linkers on antimicrobial activity. The synthesized compounds showed strong antimicrobial activity against a panel of both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). While the linker geometry showed only a modest correlation with antimicrobial activity, several of the synthesized bisQACs are promising potential antiseptics due to good antimicrobial activity (MIC≤2 μM) and their higher therapeutic indices compared to previously reported QACs.     

Metallocene QACs: The Incorporation of Ferrocene Moieties into monoQAC and bisQAC Structures

Inspired by the incorporation of metallocene functionalities into a variety of bioactive structures, particularly antimicrobial peptides, we endeavored to broaden the structural variety of quaternary ammonium compounds (QACs) by the incorporation of the ferrocene moiety. Accordingly, 23 ferrocene-containing mono- and bisQACs were prepared in high yields and tested for activity against a variety of bacteria, including Gram-negative strains and a panel of clinically isolated MRSA strains. Ferrocene QACs were shown to be effective antiseptics with some displaying single-digit micromolar activity against all bacteria tested, demonstrating yet another step in the expansion of structural variety of antiseptic QACs.     

Quaternized poly(phenylene oxide) anion exchange membrane for alkaline direct methanol fuel cells in KOH‐free media

A series of anion exchange membrane (AEM) electrolytes with quaternary ammonium moiety are fabricated from poly (phenylene oxide) for its application in alkaline direct methanol fuel cells (ADMFCs). In the first step, poly(phenylene oxide) (PPO) is successfully chloromethylated by substituting chloromethyl groups in the aryl position of polymer. In the second step, the chloromethylated PPO (CPPO) is further homogeneously quaternized and ion‐exchanged to form an AEM. From the second step, series of AEMs are prepared by changing the mole ratio of amine in relation to CPPO. The presence of quaternary ammonium group in the membrane was confirmed by elemental analysis. The fabricated membranes are subjected to cell polarization studies in ADMFCs, wherein quaternized poly(2,6‐dimethyl‐1,4‐phenylene oxide) (CPPO:amine of 1:8) membrane exhibits higher peak power density of 3.5 mW cm^?2 when compared with the other ratios of CPPO:amine in the absence of KOH solution. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43693.     

Synthesis and Antibacterial Activity of Novel Amido-Amine-Based Cationic Gemini Surfactants

A series of novel cationic gemini surfactants were synthesized from corresponding amido-amines in a single step reaction. The amido-amines were obtained from long chain carboxylic acids and 3-N,N-dimethylamino-1-propyl-amine with excellent isolated yield (up to 95 %). All the synthesized quaternary ammonium compounds (QACs) were further investigated for surface active properties. The critical micelle concentration (CMC) and the effectiveness of surface tension reduction were determined. The surface tension measurements of newly synthesized gemini surfactants showed good water solubility, and low CMC values, had great efficiency in lowering the surface tension and a strong adsorption at the air/water interface than the corresponding monomeric surfactants. Further, the antibacterial activity of the synthesized QACs against both Gram-positive and Gram-negative bacteria was also investigated.     

Antibacterial and Bacterium Adsorbing Macromolecules

Currently studies on antibacterial macromolecules, i. e., bactericidal and bacteriostatic ones, have been made to develop a new utilization field of polymeric materials. In these studies, there are immobilizations of iodine to quaternary ammonium salts, antibiotics, antibacterial groups to macromolecular substances, as well as syntheses of polymers with quaternary ammonium salts, biguanide groups, quaternary pyridinium salts, sulphonium salts, phosphonium salts, and other antibacterial groups. On the other hand, studies have been made of bacterium adsorbing macromolecules, which can remove by adsorbing bacterial cells in water. The macromolecules are the ones based on poly(4‐vinylpyridine‐co‐divinylbenzene), crosslinked poly(3‐ and 4‐chloromethylated styrene‐g‐amine), and poly(glycidyl methacrylate‐g‐amine), as well as filters and microporous membranes are covered with a macromolecule based on quaternized poly(4‐vinylpyridine‐co‐styrene). Here, a review is made of the syntheses and preparation of the respective macromolecules, as well as of their antibacterial activities and the bacterium adsorbing activities.     

Preparation of breathable polyurethane membranes with quaternary ammonium salt diols providing durable antibacterial property

Aim of this study was to produce hydrophilic breathable polyurethane membranes providing antibacterial property permanently by incorporation of a quaternary ammonium salt diol (QAS). The study was carried out by synthesis of nine different polyurethanes by solution polymerization through variations of their QAS and isocyanate contents. Fully amorphous membranes at a thickness of ~30 μm were produced from the synthesized polymers and their thermal and morphological characteristics were determined. The effect of morphological structures on the membrane water vapor transmission rates (WVTR) and antibacterial properties were correlated. The WVTR increased with the increased temperature in all membranes over 10–40 °C, all produced membranes showed water resistance up to a pressure of 2100 cmH2O and WVTR values above 60 g/m² h at 30 °C. The WVTR increased by increasing amount of QAS including cationic groups and decreased by increasing isocyanate amount reducing the molecular chain flexibility. In addition, while the unmodified membranes did not show any antibacterial activity, the QAS-added membranes provided significant inactivation against Staphylococcus aureus and Escherichia coli of about 104 CFU within 5 h of contact time. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47133.     

Imidazolium functionalized poly(vinyl alcohol) membranes for direct methanol alkaline fuel cell applications

In this study, imidazolium functionalized poly(vinyl alcohol) (PVA) was synthesized by acetalization and direct quaternization reaction. Afterwards, composite anion exchange membranes based on imidazolium‐ and quaternary ammonium‐ functionalized PVA were used for direct methanol alkaline fuel cell applications. ¹H NMR and Fourier transform infrared spectroscopy data indicated that imidazole functionalized PVA was successfully synthesized. Inductively coupled plasma mass spectrometry data demonstrated that the imidazolium structure was efficiently obtained by direct quaternization of the imidazole group. Composite anion exchange membranes were fabricated by application of the functionalized PVA solution on the surface of porous polycarbonate (PC) membranes. Fuel cell related properties of all prepared membranes were investigated systematically. The imidazolium functionalized composite membrane (PVA‐Im/PC) exhibited higher ionic conductivity (7.8 mS cm^?1 at 30 °C) despite a lower water uptake and ion exchange capacity value compared to that of quaternary ammonium. In addition, PVA‐Im/PC showed the lowest methanol permeation rate and the highest membrane selectivity as well as high alkaline and oxidative stability. Dynamic mechanical analysis results reveal that both composite membranes were mechanically resistant up to 10⁷ Pa at 140 °C. The superior performance of imidazolium functionalized PVA composite membrane compared to quaternary ammonium functionalized membrane makes it a promising candidate for direct methanol alkaline fuel cell applications. © 2020 Society of Chemical Industry     

Removal of N‐butanol from aqueous solutions by ion–exchange membranes containing organic counterions

The pervaporation of aqueous butanol solutions was investigated using thin‐film composite membranes composed of a poly(vinylidene fluoride) substrate coated with a sulfonated poly(2,6‐dimethyl‐1,4‐phenelene oxide) polymer. The polymer was ion‐exchanged with quaternary ammonium cations having aliphatic substituents of various chain lengths. The pervaporation of aqueous n‐butanol solutions using these membranes gave a permeate more concentrated in n‐butanol; therefore, they were alcohol‐selective. The separation factor increased and the permeate flux decreased as the chain lengths of the aliphatic substituents were increased. Hence, the mass‐transport properties of such membranes can be controlled or altered to yield some desired permselectivity by the introduction of a proper counterion. It was observed that the n‐butanol flux was small relative to the total flux and, therefore, the water flux dominated the total permeate flux. The degree of swelling of the membranes and its effect on membrane performance was investigated as well. As the n‐butanol content was increased, the swelling of the membranes increased greatly. High membrane swelling caused a reduction in the separation factor. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 47–58, 1999     

Preparation of composite anion exchange membranes based on in-situ copolymerization of N-vinyl formamide and divinylbenzene in porous PTFE

A series of composite anion exchange membranes was synthesized via in-situ copolymerization of various ratios N-vinyl formamide (NVF) and divinylbenzene (DVB), supported by porous polytetrafluoroethylene (PTFE) polymer matrix, and followed by alkaline hydrolysis, and quaternization of the composite membranes with epoxypropyltrimethylammonium chloride (EPTMAC). FTIR and SEM analyses revealed that the composite membranes were successfully prepared. Moreover, the hydrophilic property of the composite membrane improved by introduction of the quaternized poly(NVF-co-DVB) copolymer. Water uptake, swelling ratio, and conductivity showed upward trends by increase of NVF amount. The copolymer with 95% of NVF showed the highest elongation at break (102%, room temperature) and conductivity (5.15 × 10⁻² S/cm, 80°C). After immersion of the PNDB_95%-N membrane in 5 mol/L NaOH solution for 96 h at room temperature, the conductivity (60°C) of the membrane decreased to 3.99 × 10⁻² S/cm. Moreover, the membrane registered weight loss under 4.5%, caused by degradation of the quaternary ammonium groups in NaOH solution. All in all, in 3 mol/L methanol solutions, the composite membranes showed permeability ranging from 7.6% to 19.7%, if compared to the Nafion®-115 membrane, showing good alcohol resistance.     

Crosslinked anion exchange membrane with improved membrane stability and conductivity for alkaline fuel cells

As a core component of anion exchange membrane (AEM) fuel cells, it has practical significance to improve the performance of AEMs. However, it is difficult to obtain AEM with both good stability and high conductivity. In this study, a series of AEMs were prepared by chloromethylation, quaternization, and crosslinking reactions. The quaternization reaction was carried out first to ensure that there are abundant quaternary ammonium groups on AEM and enhance the conductivity of membrane. N,N,N′,N′-tetramethylethylenediamine was used as a crosslinker to improve membrane stability and mechanical property. A simple, mild, and cost-effective AEM synthetic route was developed. This strategy achieves a certain balance of electrochemical and physical properties. The effect of the crosslinking reactions on the property of membrane was evaluated. Crosslinked membranes have better dimensional stability (water uptake: 20.2% and swelling ratio: 2.1%), mechanical properties (55.84 MPa), and alkaline stability because crosslinked structures result in large steric hindrance. The mutually independent quaternization and crosslinking reaction do not affect the electrochemical performance of membranes; in the crosslinking reaction stage, crosslinker also reacted as quaternization agent and increased the number of reactive groups in AEM. Thus, the resulting crosslinked AEM exhibits higher ion exchange capacity and ionic conductivities (46.4 mS cm⁻¹). © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 48169.     

Novel anion exchange membranes having fluorocarbon backbone: Preparation and stability

Anion exchange membranes with excellent durability were prepared by chemical modification of Nafion. The modification was achieved by transformation of the sulfonic acid group into quaternary ammonium group. Namely, Nafion membrane was first converted into an amide-type membrane. Reduction of the carbonxyl group to methylene followed by quaternarization with alkyl iodide resulted in the formation of an anion exchange membrane. The electric resistance of the resulting membranes depends on the equivalent weight of the starting membranes (4.4–6.0 Ω cm² in 0.5N NaCl). The characteristics of the membranes are the excellent stability toward chemical substances such as organic solvents, oxidizing agents, acids, etc. For example, the membranes are stable in aqueous saturated chlorine solution at 60°C for 1000 hr.     

Multilayer composite surfaces prepared by an electrostatic self‐assembly technique with quaternary ammonium salt and poly(acrylic acid) on poly(acrylonitrile‐co‐acrylic acid) membranes

An electrostatic self‐assembly technique was applied to prepare ion complex polymer layers on polyacrylonitrile with acrylic acid segments {poly(acrylonitrile‐co‐acrylic acid) [P(AN‐co‐AA)]}. For the ionic complex layers, quaternary ammonium salts, such as cetyl trimethyl ammonium chloride (CTAC) and tetramethyl ammonium chloride (TMAC), were used as cationic species, and also, poly(acrylic acid) (PAA) was used as an anionic species. These cationic and anionic species were self‐assembled alternately on the surface of the P(AN‐co‐AA) membrane. Fourier transform infrared spectroscopy, AFM, and water contact angle measurements of the membrane surface were used to confirm the formation of the multilayer composites on the P(AN‐co‐AA). The permeabilities of water and macromolecules of different molecular weights were evaluated by a membrane filtration technique. The values of permeability strongly depended on the formation layer by layer of these ion composites on the base P(AN‐co‐AA). Through the measurement of the values of the contact angle of water, it was clear that surface nature of the base membrane treated by CTAC or TMAC and PAA dramatically changed. We concluded that such an electrostatic self‐assembly technique is useful for the preparation of multicomposite layers to modify the surface of base P(AN‐co‐AA) membranes. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Antibacterial activity of novel insoluble bead‐shaped polymer‐supported multiquaternary ammonium salts

This study describes the effect of antibacterial activity of newly reported five different novel insoluble bead‐shaped polymer‐supported multiquaternary ammonium salts (PM quats) viz., bis‐quat, tris‐quat (2 Nos.), tetrakis‐quat, hexakis‐quat containing two, three, four, and six quaternary ammonium groups, respectively. The presence of number of quaternary ammonium groups in each salt was established already through Fourier‐transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, and chloride ion analyzes. The antibacterial activities of these five different PM quats against three different bacteria viz., Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa were investigated by serial dilution and spread plate method and compared the same with a monoquat containing single quaternary ammonium group. The extent of antibacterial activity has been measured in terms of colony forming units (CFU) at different time intervals. The observed results show that all the PM quats exhibited excellent‐antibacterial activity against each bacterium. On the basis of the CFU values, the antibacterial activity was found to increase from bis‐quat to hexakis‐quat, which reveals that the activity of PM quats increases with increase in the number of quaternary ammonium groups. The mechanism of interaction of quats with bacterial cytoplasmic membrane has been explained as an adsorption‐like phenomenon. The reusability of highly active hexakis‐quat against Staphylococcus aureus was studied and the activity was found to reduce after first cycle. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010