Fundamental importance of ionic interactions in the liquid phase: A review of recent studies of ionic liquids in biomedical and pharmaceutical applications

The continued emergence of antibiotic-resistant organisms has severely depleted our arsenal of effective antimicrobials. Ionic liquids (ILs) show great promise as antibacterial agents but understanding the mechanism of attack on bacterial cells is key to ensuring that design of IL-based biocides impart maximum efficacy with minimal toxicity, while also avoiding the potential for the target organisms to become resistant. Here we report the antibacterial attributes of a set of choline and geranate (CAGE)-based ILs and identify the mechanism by which they interact with the Gram-negative cell wall of Escherichia coli. CAGE is envisaged as an antimicrobial agent to treat topical infections in skin. Our earlier work has shown that CAGE is highly effective across a breadth of bacterial, fungal, and viral species and is benign to human cells. This combination makes CAGE an ideal antimicrobial for human use. Four CAGE variants with varying ratios of choline and geranic acid were synthesized and tested for their an...

Mechanism of Antibacterial Activity of Choline-Based Ionic Liquids (CAGE)

Ionic liquids (ILs) are a relatively new class of organic electrolytes composed of an organic cation and either an organic or inorganic anion, whose melting temperature falls around room-temperature. In the last 20 years, the toxicity of ILs towards cells and micro-organisms has been heavily investigated with the main aim to assess the risks associated with their potential use in (industrial) applications, and to develop strategies to design greener ILs. Toxicity, however, is synonym with affinity, and this has stimulated, in turn, a series of biophysical and chemical-physical investigations as well as few biochemical studies focused on the mechanisms of action (MoAs) of ILs, key step in the development of applications in bio-nanomedicine and bio-nanotechnology. This review has the intent to present an overview of the state of the art of the MoAs of ILs, which have been the focus of a limited number of studies but still sufficient enough to provide a first glimpse on the subject. The overall picture that emerges is quite intriguing and shows that ILs interact with cells in a variety of different mechanisms, including alteration of lipid distribution and cell membrane viscoelasticity, disruption of cell and nuclear membranes, mitochondrial permeabilization and dysfunction, generation of reactive oxygen species, chloroplast damage (in plants), alteration of transmembrane and cytoplasmatic proteins/enzyme functions, alteration of signaling pathways, and DNA fragmentation. Together with our earlier review work on the biophysics and chemical-physics of IL-cell membrane interactions (Biophys. Rev. 9:309, 2017), we hope that the present review, focused instead on the biochemical aspects, will stimulate a series of new investigations and discoveries in the still new and interdisciplinary field of “ILs, biomolecules, and cells.”

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Mechanisms of action of ionic liquids on living cells: the state of the art

Empirical evidence and conceptual elaboration reveal and rationalize the remarkable affinity of organic ionic liquids for biomembranes. Cations of the so-called room-temperature ionic liquids (RTILs), in particular, are readily absorbed into the lipid fraction of biomembranes, causing a variety of observable biological effects, including generic cytotoxicity, broad antibacterial potential, and anticancer activity. Chemical physics analysis of model systems made of phospholipid bilayers, RTIL ions, and water confirm and partially explain this evidence, quantifying the mild destabilizing effect of RTILs on the structural, dynamic, and thermodynamic properties of lipids in biomembranes. Our Feature Article presents a brief introduction to these systems and to their roles in biophysics and biotechnology, summarizing recent experimental and computational results on their properties. More importantly, it highlights the many developments in pharmacology, biomedicine, and bionanotechnology expected from the curre...

Room-Temperature Ionic Liquids and Biomembranes: Setting the Stage for Applications in Pharmacology, Biomedicine, and Bionanotechnology

Room-temperature ionic liquids (RTIL) are a new class of organic salts whose melting temperature falls below the conventional limit of 100 °C. Their low vapor pressure, moreover, has made these ionic compounds the solvents of choice of the so-called green chemistry. For these and other peculiar characteristics, they are increasingly used in industrial applications. However, studies of their interaction with living organisms have highlighted mild to severe health hazards. Since their cytotoxicity shows a positive correlation with their lipophilicity, several chemical-physical studies of their interactions with biomembranes have been carried out in the last few years, aiming to identify the molecular mechanisms behind their toxicity. Cation chain length and anion nature of RTILs have seemed to affect lipophilicity and, in turn, their toxicity. However, the emerging picture raises new questions, points to the need to assess toxicity on a case-by-case basis, but also suggests a potential positive role of RTILs in pharmacology, bio-medicine and bio-nanotechnology. Here, we review this new subject of research, and comment on the future and the potential importance of this emerging field of study.

Room-temperature ionic liquids meet bio-membranes: the state-of-the-art.

Ionic liquids (ILs) are important for their antimicrobial activity and are found to be toxic to some microorganisms. To shed light on the mechanism of their activities, the interaction of an imidazolium-based IL 1-butyl-3-methylimidazolium tetrfluoroborate ([BMIM][BF4]) with E. coli bacteria and cell-membrane-mimicking lipid mono- and bilayers has been studied. The survival of the bacteria and corresponding growth inhibition are observed to be functions of the concentration of the IL. The IL alters the pressure–area isotherm of the monolayer formed at an air–water interface by the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid. The in-plane elasticity of the lipid layer is reduced as a consequence of the insertion of this IL. The X-ray reflectivity study from a polymer-supported lipid bilayer shows strong perturbation in the self-assembled structure of the bilayer due to the interaction. As a consequence, there is a considerable decrease in bilayer thickness and a corresponding increase in elect...

X-ray Reflectivity Study of the Interaction of an Imidazolium-Based Ionic Liquid with a Soft Supported Lipid Membrane

Synthetic organic molecules, which can selectively convert excess intracellular copper (Cu) ions to nanozymes with an ability to protect cells from oxidative stress, are highly significant in developing therapeutic agents against Cu-related disorder like Wilson's disease. Here, we report 1,3-bis(2-hydroxyethyl)-1 H-benzoimidazole-2-selenone (1), which shows a remarkable ability to remove Cu ion from glutathione, a major cytosolic Cu-binding ligand, and thereafter converts it into copper selenide (CuSe) nanozyme that exhibits remarkable glutathione peroxidase-like activity, at cellular level of H2O2 concentration, with excellent cytoprotective effect against oxidative stress in hepatocyte. Cu-driven deselenization of 1, under physiologically relevant conditions, occurred in two steps. The activation of C═Se bond by metal ion is the crucial first step, followed by cleavage of the metal-activated C═Se bond, initiated by the OH group of N-(CH2)2OH substituent through neighboring group participation (deselenization step), resulted in the controlled synthesis of various types of Cu2-xSe nanocrystals (NCs) (nanodisks, nanocubes, and nanosheets) and tetragonal Cu3Se2 NCs, depending upon the oxidation state of the Cu ion used to activate the C═Se bond. Deselenization of 1 is highly metal-selective. Except Cu, other essential metal ions, including Mn2+, Fe2+, Co2+, Ni2+, or Zn2+, failed to produce metal selenide under identical reaction conditions. Moreover, no significant change in the expression level of Cu-metabolism-related genes, including metallothioneines MT1A, is observed in liver cells co-treated with Cu and 1, as opposed to the large increase in the concentrations of these genes observed in cells treated with Cu alone, suggesting the participation of 1 in Cu homeostasis in hepatocyte.

Copper-Driven Deselenization: A Strategy for Selective Conversion of Copper Ion to Nanozyme and Its Implication for Copper-Related Disorders.

RUVBLs constitute a conserved group of ATPase proteins that play significant role in a variety of cellular processes including transcriptional regulation, cell cycle and DNA damage repair. Three RUVBL homologues, namely, PfRUVBL1, PfRUVBL2 and PfRUVBL3 have been identified in P. falciparum, unlike its eukaryotic counterparts, which have two RUVBL proteins (RUVBL1 & RUVBL2). The present study expands our understanding of PfRUVBL3 protein and thereby basic biology of Plasmodium in general. Here, we have shown that parasite PfRUVBL3 is a true homolog of human/yeast RUVBL2 protein. Our result show that PfRUVBL3 constitutively expresses throughout the stages of intra-erythrocytic cycle (IDC) with varied localization. In addition to ATPase and oligomerization activity, we have for the first time shown that PfRUVBL3 possess DNA cleavage activity which interestingly is dependent on its insertion domain. Furthermore, we have also identified RUVBL3 to be an interacting partner of an essential chromatin remodeling protein PfMYST and together they colocalize with H3K9me1 histone in parasitophorous vacuole during the ring stage of IDC suggesting their potential involvement in chromatin remodeling and gene transcription.

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Plasmodium falciparum RUVBL3 protein: a novel DNA modifying enzyme and an interacting partner of essential HAT protein MYST

Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.e., 1-aryltetrahydro/dihydro-β-carbolines and piperidine/pyrrolidine-fused indole derivatives, for their in vitro anti-plasmodial activity. Trifluoroacetic acid catalyzed transformation involving tryptamine and various aldehydes/ketones provided the library. Among all the compounds screened, 1-aryltetrahydro-β-carbolines 2 and 3 displayed significant anti-plasmodial activity against both the artemisinin-sensitive and artemisinin-resistant strain of Plasmodium falciparum. It was observed that these compounds inhibited the overall parasite growth in intra-erythrocytic developmental cycle (IDC) via reactive oxygen species-mediated parasitic death and thus could be potential anti-malarial compounds. Overall the compounds 2 and 3 identified in this study shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemisinin-resistant strains of P. falciparum.

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Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum.

In order to survive and establish infection, Plasmodium parasite employ various strategies to evade host immune response. Var genes family, a repertoire of 60 genes, express parasite-specific protein PfEMP1, a variable surface antigen, on the membrane of infected erythrocyte, and by continuously switching the variants of PfEMP1, helps the parasite to avoid detection and destruction by host immune system during intra-erythrocytic developmental cycle. Although chromatin modifications are recognized to be a prominent phenomenon in regulation of mono-allelic expression of these var genes, however the precise histone codes and molecular players & mechanisms guiding these modifications are yet to be unravelled in depth. In this study, we have functionally characterized RUVBL proteins of P. falciparum and shown that PfMYST (an essential lysine acetyl transferase) and PfRUVBL protein complex occupy the TARE region and var gene promoter in ring stage of the parasite. Further we have demonstrated that PfMYST/PfRUVBL complex interact with core histone, H3 & H4. Overall the findings of this study adds a layer by identifying the potential role of epigenetic regulators, PfMYST & PfRUVBL in regulation of monoallelic expression of var genes in malaria parasite.

Himani Saxena

Papers

X-ray Reflectivity Study of the Interaction of an Imidazolium-Based Ionic Liquid with a Soft Supported Lipid Membrane

Copper-Driven Deselenization: A Strategy for Selective Conversion of Copper Ion to Nanozyme and Its Implication for Copper-Related Disorders.

Plasmodium falciparum RUVBL3 protein: a novel DNA modifying enzyme and an interacting partner of essential HAT protein MYST

Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum.

P. falciparum PfRUVBL proteins binds at TARE region and var gene promoter located in subtelomeric region.