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Membrane destabilization (% ± SD) as obtained by the calcein fluorescent die released from PE:PC:PS:CHO (1:1:1:1) liposomes, for the indicated surfactant concentrations. Experiments were conducted at room temperature. doi:10.1371/journal.pone.0026965.g003
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Dicationic alkylammonium bromide gemini surfactants represent a class of amphiphiles potentially effective as skin permeation enhancers. However, only a limited number of studies has been dedicated to the evaluation of the respective cytotoxicity, and none directed to skin irritation endpoints. Supported on a cell viability study, the cytotoxicity...
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Context 1
... shown in Figure 3, it is clearly observed that gemini sur- factants are generally more effective in promoting membrane destabilization than DTAB. Following an order of increasing effect, one has the 14-2-14, 12-2-12 and 12-10-12 gemini, with the latter placed drastically above the others. ...
Citations
... This, in turn, may interfere with the adhesion of pathogens and prevent the formation of biofilms or lead to their eradication 72 . In addition, gemini QAS have a greater ability to penetrate the cell envelopes of microorganisms than their monomeric counterparts 73 . ...
Newly synthesized gemini quaternary ammonium salts (QAS) with different counterions (bromide, hydrogen chloride, methylcarbonate, acetate, lactate), chain lengths (C12, C14, C16) and methylene linker (3xCH2) were tested. Dihydrochlorides and dibromides with 12 carbon atoms in hydrophobic chains were characterized by the highest biological activity against planktonic forms of yeast and yeast-like fungi. The tested gemini surfactants also inhibited the production of filaments by C. albicans. Moreover, they reduced the adhesion of C. albicans cells to the surfaces of stainless steel, silicone and glass, and slightly to polystyrene. In particular, the gemini compounds with 16-carbon alkyl chains were most effective against biofilms. It was also found that the tested surfactants were not cytotoxic to yeast cells. Moreover, dimethylcarbonate (2xC12MeCO3G3) did not cause hemolysis of sheep erythrocytes. Dihydrochlorides, dilactate and diacetate showed no mutagenic potential.
... In addition, other studies suggest a positive correlation between the length of the alkyl chain of surfactants and the ability to eradicate biofilms. High concentrations of surfactant compounds with fungicidal activity lead to the disintegration of the biofilm structure, which may be associated with micellization if the concentration exceeds the CMC [56]. ...
The current trend in microbiological research aimed at limiting the development of biofilms of multidrug-resistant microorganisms is increasingly towards the search for possible synergistic effects between various compounds. This work presents a combination of a naturally occurring compound , β-aescin, newly synthesized alkylamidobetaines (AABs) with a general structure-C n TMDAB, and antifungal drugs. The research we conducted consists of several stages. The first stage concerns determining biological activity (antifungal) against selected multidrug-resistant strains of Candida glabrata (C. glabrata) with the highest ability to form biofilms. The second stage of this study determined the activity of β-aescin combinations with antifungal compounds and alkylamidobetaines. In the next stage of this study, the ability to eradicate a biofilm on the polystyrene surface of the combination of β-aescin with alkylamidobetaines was examined. It has been shown that the combination of β-aescin and alkylamidobetaine can firmly remove biofilms and reduce their viability. The last stage of this research was to determine the safety regarding the cytotoxicity of both β-aescin and alkylamidobetaines. Previous studies on the fibroblast cell line have shown that C9 alkylamidobetaine can be safely used as a component of anti-biofilm compounds. This research increases the level of knowledge about the practical possibilities of using anti-biofilm compounds in combined therapies against C. glabrata.
... Reactive oxygen species can lead to the beta-oxidation of fatty acids found in cell membranes and increase their permeability and disruptions. In this way, they can lead to a disturbance of the cell's ionic balance (the leakage of Na + and K + ions) [17]. Microcomposites can also act directly on the surface of bacteria and lead to alkylation of surface proteins. ...
Silver phosphate and its composites have been attracting extensive interest as photocatalysts potentially effective against pathogenic microorganisms. The purpose of the present study was to investigate the mechanism of bactericidal action on cells of opportunistic pathogens. The Ag 3 PO 4 /P25 (AGP/P25) and Ag 3 PO 4 /HA (HA/AGP) powders were prepared via a co-precipitation method. Thereafter, their antimicrobial properties against Enterococcus faecalis, Staphylococcus epidermidis, and Staphylococcus aureus (clinical and reference strains) were analyzed in the dark and after exposure to visible light (VIS). The mechanism leading to cell death was investigated by the leakage of metabolites and potassium ions, oxidative stress, and ROS production. Morphological changes of the bacterial cells were visualized by transmission electron microscopy (TEM) and scanning transmission electron microscopy with energy-dispersive X-ray spectroscopy (SEM EDS) analysis. It has been shown that Ag 3 PO 4-based composites are highly effective agents that can eradicate 100% of bacterial populations during the 60 min photocatalytic inactivation. Their action is mainly due to the production of hydroxyl radicals and photogenerated holes which lead to oxidative stress in cells. The strong affinity to the bacterial cell wall, as well as the well-known biocidal properties of silver itself, increase undoubtedly the antimicrobial potential of the Ag 3 PO 4-based composites.
... Generally, amphiphiles are known to influence the organisation of lipid membranes, and surfactants have been extensively studied in systems involving interactions with lipid membranes [87]. Above a certain concentration, these compounds may exhibit undesirable properties, including toxicity. ...
... Almeida et al. studied the cytotoxicity of gemini surfactants and suggested that the toxicity increases with increasing spacer length and that surfactants with longer tails are less toxic than those with shorter tails [87]. They chose the NCTC 2544 cell line, a human skin keratinocyte cell line, as a model of skin irritation. ...
... After 24 h of exposure to low concentrations of 12-6-12 (up to 10 mM), no significant cytotoxicity was observed in the cell line. However, at a 12-6-12 concentration of 50 mM, strong toxicity was observed [87]. The cytotoxicity and skin irritation profiles of 12-6-12 were also studied by Silva et al. [89]. ...
Surfactants are amphiphilic molecules and one of the most versatile products of the chemical industry. They can be absorbed at the air–water interface and can align themselves so that the hydrophobic part is in the air while the hydrophilic part is in water. This alignment lowers the surface or interfacial tension. Gemini surfactants are a modern variety of surfactants with unique properties and a very wide range of potential applications. Hexamethylene-1,6-bis(N-dodecyl-N,N-dimethylammonium bromide) is one such representative compound that is a better alternative to a single analogue. It shows excellent surface, antimicrobial, and anticorrosion properties. With a highly efficient synthetic method and a good ecological profile, it is a potential candidate for numerous applications, including biomedical applications.
... Generally, amphiphiles are known to influence the organisation of lipid membranes, and surfactants have been extensively studied in systems involving interactions with lipid membranes [87]. Above a certain concentration, these compounds may exhibit undesirable properties, including toxicity. ...
... Almeida et al. studied the cytotoxicity of gemini surfactants and suggested that the toxicity increases with increasing spacer length and that surfactants with longer tails are less toxic than those with shorter tails [87]. They chose the NCTC 2544 cell line, a human skin keratinocyte cell line, as a model of skin irritation. ...
... After 24 h of exposure to low concentrations of 12-6-12 (up to 10 mM), no significant cytotoxicity was observed in the cell line. However, at a 12-6-12 concentration of 50 mM, strong toxicity was observed [87]. The cytotoxicity and skin irritation profiles of 12-6-12 were also studied by Silva et al. [89]. ...
Surfactants are amphiphilic molecules and one of the most versatile products of the chemical industry. They can be absorbed at the air-water interface and can align themselves so that the hydrophobic part is in the air while the hydrophilic part is in water. This alignment lowers the surface or interfacial tension. Gemini surfactants are a modern variety of surfactants with unique properties and a very wide range of potential applications. Hexamethylene-1,6-bis(N-dodecyl-N,N-dimethylammonium bromide) is one such representative compound that is a better alternative to a single analogue. It shows excellent surface, antimicrobial, and anticorrosion properties. With a highly efficient synthetic method and a good ecological profile, it is a potential candidate for numerous applications, including biomedical applications.
... Gemini-TAB surfactants interacting with DPPC: Chol (dipalmitoyl phosphatidylcholine-cholesterol) liposome membrane models were also found to cause membrane disruption dependent upon the length of the acyl chains of the TAB and the spacer length between the head-groups (Almeida et al., 2011). It was found that surfactants with chain lengths similar to the phospholipid chain lengths caused less disruption to the membrane structure than those with shorter chains, which may indicate why a larger fraction of the longer-chain surfactants is required to cause membrane disruption sufficient to inhibit cell growth. ...
... Further morphological studies using 31 P NMR and molecular dynamics (MD) simulations indicated that differences in the disruption caused by varying chain and spacer lengths could be caused by packing differences in the membrane (Almeida et al., 2011). The length of hydrophobic components influences their shape upon insertion into membranes and therefore the membrane curvature and packing of the lipid molecules (Fig. 1). ...
The control of microorganisms is a key objective in disease prevention and in medical, industrial, domestic and food-production environments. Whilst the effectiveness of biocides in these contexts is well-evidenced, debate continues about the resistance risks associated with their use. This has driven an increased regulatory burden, which in turn could result in a reduction of both the deployment of current biocides and the development of new compounds and formulas. Efforts to balance risk and benefit are therefore of critical importance and should be underpinned by realistic methods and a multi-disciplinary approach, and through objective and critical analyses of the literature. The current literature on this topic can be difficult to navigate. Much of the evidence for potential issues of resistance generation by biocides is based on either correlation analysis of isolated bacteria, where reports of treatment failure are generally uncommon, or laboratory studies that do not necessarily represent real biocide applications. This is complicated by inconsistencies in the definition of the term resistance. Similar uncertainties also apply to co-resistance between biocides and antibiotics. Risk assessment studies that can better inform practice are required. The resulting knowledge can be utilised by multiple stakeholders including those tasked with new product development, regulatory authorities, clinical practitioners, and the public. This review considers current evidence for resistance and co-resistance and outlines efforts to increase realism in risk assessment. This is done in the background of the discussion of the mode of application of biocides and the demonstrable benefits as well as the potential risks.
... The EU ban on animal testing forced the development of new alternative methods for assessing the skin-irritation potential [34]. Thus, for preliminary studies of the irritation potential of (bio)surfactants intended for use in cosmetic products, their effect on the model lipid bilayers of liposomes, or cytotoxicity tests towards the cultured skin cells are employed [35,36]. This study aims to compare the irritation potential of four popular synthetic surfactants and the soapwort aqueous extract on human skin models. ...
Our skin is continuously exposed to different amphiphilic substances capable of interaction with its lipids and proteins. We describe the effect of a saponin-rich soapwort extract and of four commonly employed synthetic surfactants: sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), ammonium lauryl sulfate (ALS), cocamidopropyl betaine (CAPB) on different human skin models. Two human skin cell lines were employed: normal keratinocytes (HaCaT) and human melanoma cells (A375). The liposomes consisting of a dipalmitoylphosphatidylcholine/cholesterol mixture in a molar ratio of 7:3, mimicking the cell membrane of keratinocytes and melanoma cells were employed as the second model. Using dynamic light scattering (DLS), the particle size distribution of liposomes was analyzed before and after contact with the tested (bio)surfactants. The results, supplemented by the protein solubilization tests (albumin denaturation test, zein test) and oil emulsification capacity (using olive oil and engine oil), showed that the soapwort extract affects the skin models to a clearly different extent than any of the tested synthetic surfactants. Its protein and lipid solubilizing potential are much smaller than for the three anionic surfactants (SLS, ALS, SLES). In terms of protein solubilization potential, the soapwort extract is comparable to CAPB, which, however, is much harsher to lipids.
... In comparison to conventional surfactants, they have higher surface activity i.e. micellization behavior, efficiency in reducing interfacial tension and solubility [18][19][20][21][22][23]. The micro-environment and micellization process of surfactants are mainly influenced by the existence of additives for instance carbohydrates, drugs, electrolytes, amino acids, etc. along with alteration in experimental conditions [24][25][26][27]. Since the basic property of most of the drugs is low solubility in water, the utilization of micelles for the solubilization of drugs has fascinated a great deal of attention in the last decade [28][29][30]. ...
In the present work, we investigated the effect of drug Betaine Hydrochloride (Betaine HCl) on the aggregation behavior of ethylene-1, 2-bis (N, N-dimethyl-N-tetradecylammonium bromide) (14-2-14) and tetradecyltrimethylammonium bromide (TTAB) by employing electrical conductivity and FT-IR spectroscopic techniques. Initially, synthesis of 14-2-14 is carried out in laboratory followed by determination of critical micelle concentration (CMC) through electrical conductivity measurements at temperatures 293.15K, 298.15K, 303.15K, 308.15K in absence and presence of Betaine HCl at concentrations 0.10mmol/kg, 0.15mmol/kg and 0.25mmol/kg. The decrement in CMC value is observed with increasing concentrations of Betaine HCl as well as with increasing temperatures. Several thermodynamic parameters such as the standard enthalpy of micellization (ΔH⁰m), the standard entropy of micellization ((ΔS⁰m)) and the standard Gibbs energy of micellization (ΔG⁰m), etc. have been evaluated using values of CMC for various concentrations of Betaine HCl at different temperatures. The alterations instigated in respective have been recognized by FT-IR spectroscopic analysis, which signifies the variations produced by the drug on the aggregation of the surfactants (14-2-14 and TTAB) in aqueous media.
... Research carried out to date suggests a positive correlation between the ability to eradicate biofilm and the length of the alkyl chain. High concentrations of surfactants could have a fungicidal effect and lead to disintegration of biofilm structure, which in the case of concentrations exceeding CMC (critical micelization concentration) could be assisted by micelization 20 . Further research carried out in this study concerning the impact of multifunctional cationic surfactants on vitality of the cells has shown its significant decrease after treatment with surfactants, especially dimethylamine derivates. ...
Our research aims to expand the knowledge on relationships between the structure of cationic dicephalic surfactants—N,N-bis[3,3_-(dimethylamine)propyl]alkylamide dihydrochlorides and N,N-bis[3,3_-(trimethylammonio)propyl]alkylamide dibromides (alkyl: n-C9H19, n-C11H23, n-C13H27, n-C15H31)—and their antifungal mechanism of action on Candida albicans. The mentioned groups of amphiphilic substances are characterized by the presence of a weak, hydrochloride cationic center readily undergoing deprotonation, as well as a stable, strong quaternary ammonium group and alkyl chains capable of strong interactions with fungal cells. Strong fungicidal properties and the role in creation and eradication of biofilm of those compounds were discussed in our earlier works, yet their mechanism of action remained unclear. It was shown that investigated surfactants induce strong oxidative stress and cause increase in cell membrane permeability without compromising its continuity, as indicated by increased potassium ion (K⁺) leakage. Thus experiments carried out on the investigated opportunistic pathogen indicate that the mechanism of action of the researched surfactants is different than in the case of the majority of known surfactants. Results presented in this paper significantly broaden the understanding on multifunctional cationic surfactants and their mechanism of action, as well as suggest their possible future applications as surface coating antiadhesives, fungicides and antibiofilm agents in medicine or industry.
... The toxicity of the surfactants, however, could grow with increasing the length of the alkyl chain, potentially influenced by the double-positive charge associated with hydrophilic groups and stronger interaction with biological membranes resulting from it. The length of the alkyl chain has an impact on CMC (critical micellization concentration) and on antibacterial activity as well (Almeida et al. 2011;Paluch et al. 2018;Piętka-Ottlik et al. 2012). Many of the newly synthetised cationic surfactants have found application in industry, medicine and agriculture, mainly as preservatives, disinfectants and plant-protective agents (Bazylińska et al. 2016;Farn 2008;Pérez et al. 2005;Shrestha et al. 2017). ...
Our research aimed to expand the knowledge of relationships between the structure of multifunctional cationic dicephalic surfactants with a labile linker—N,N-bis[3,3-(dimethylamine)propyl]alkylamide dihydrochlorides and N,N-bis[3,3-(trimethylammonio)propyl]alkylamide dibromides (alkyl: n-C9H19, n-C11H23, n-C13H27, n-C15H31)—and their possible mechanism of action on fungal cells using the model organism Saccharomyces cerevisiae. General studies performed on surfactants suggest that in most cases, their main mechanism of action is based on perforation of the cell membranes and cell disruption. Experiments carried out in this work with cationic dicephalic surfactants seem to modify our understanding of this issue. It was found that the investigated compounds did not cause perforation of the cell membrane and could only interact with it, increasing its permeability. The surfactants tested can probably penetrate inside the cells, causing numerous morphological changes, and contribute to disorders in the lipid metabolism of the cell resulting in the formation of lipid droplet aggregates. This research also showed that the compounds cause severe oxidative stress within the cells studied, including increased production of superoxide anion radicals and mitochondrial oxidative stress. Dicephalic cationic surfactants due to their biodegradability do not accumulate in the environment and in the future may be used as effective antifungal compounds in industry as well as medicine, which will be environmentally friendly.
Key points
• Dicephalic cationic surfactants do not induce disruption of the cell membrane.
• Surfactants could infiltrate into the cells and cause accumulation of lipids.
• Surfactants could cause acute oxidative stress in yeast cells.
• Compounds present multimodal mechanism of action.
Graphical abstract
