Abstract
The complex composition of bacterial membranes has a significant impact on the understanding of pathogen function and their development towards antibiotic resistance. In addition to the inherent complexity and biosafety risks of studying biological pathogen membranes, the continual rise of antibiotic resistance and its significant economical and clinical consequences has motivated the development of numerous in vitro model membrane systems with tuneable compositions, geometries, and sizes. Approaches discussed in this review include liposomes, solid-supported bilayers, and computational simulations which have been used to explore various processes including drug-membrane interactions, lipid-protein interactions, host–pathogen interactions, and structure-induced bacterial pathogenesis. The advantages, limitations, and applicable analytical tools of all architectures are summarised with a perspective for future research efforts in architectural improvement and elucidation of resistance development strategies and membrane-targeting antibiotic mechanisms.
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Introduction
All organisms rely on the presence of biological membranes acting as barriers between the inside and outside cellular environments. The functionality of such membranes is dictated by the types of lipids and other molecules that make up their often highly complex structure (Watson 2015; Guidotti 1972).
The “ESKAPE” pathogens, a faction of Gram-negative (GN) and Gram-positive (GP) bacteria, are responsible for the majority of nosocomial infections and are deemed a great threat to global healthcare because of their multidrug resistance (MDR) (Boucher et al. 2009; Mar et al. 2017; Pendleton et al. 2013; Rice 2010; Santajit and Indrawattana 2016; Ventola 2015). MDR bacterial pathogens can overexpress intrinsic resistance markers via adaptive mutations and acquire various foreign resistance factors through gene transfer processes (Gould and Bal 2013; Ventola 2015; Chilambi et al. 2018; Fernández and Hancock 2012; Prestinaci et al. 2015; Jiang et al. 2019a). This makes them resistant to even the most effective antimicrobial medications, rendering once treatable infections untreatable (Mar et al. 2017; Renwick et al. 2016). Antimicrobial resistance has resulted in significant economic damage due to increased patient morbidity and mortality (Boucher et al. 2009; Ventola 2015; Renwick et al. 2016; Dutescu and Hillier 2021; D’Andrea et al. 2019; Tacconelli et al. 2018). Given the lack of success in marketing novel therapeutic antimicrobial agents including teixobactins, antimicrobial nanomaterials, and micro-engineered biomolecules (Mulani et al. 2019; Makabenta et al. 2021; Fatima et al. 2021; Mantravadi et al. 2019; Charbonneau et al. 2020; Hussein et al. 2020), current research has been devoted to sourcing natural antimicrobial products due to their chemical diversity and reported effectiveness as narrow- or broad-spectrum antibiotics (Hutchings et al. 2019; Quinto et al. 2019; Ghrairi et al. 2019). However, further research is required to ensure their clinical utility and to develop a better understanding of their mechanism of action. This highlights the critical requirement to understand the mechanisms behind pathogen resistance development and antimicrobial action.
The bacterial lipid membrane of MDR pathogens plays a significant part in the resistance development towards membrane-targeting antibiotics (polymyxins, β-lactams, glycopeptides, and lipopeptides), which typically penetrate the cell membrane to facilitate cellular entry of medication, or directly disrupt the cell membranes structural integrity to facilitate cell lysis (Kapoor et al. 2017; Epand et al. 2016; Tenover 2006; Dias and Rauter 2019). The membrane lipid profile can dictate the effectiveness of antibiotics and drug-efflux proteins that mediate the expulsion of antibiotics from the bacterium. Pathogen adaptation mechanisms alter the native lipid composition which facilitates structural modifications, including changes in membrane fluidity, organisation, and packing, that circumvents the effects of antibiotics and evades host immune attack (Jiang et al. 2019a, 2019b; Dadhich and Kapoor 2020; Han et al. 2018; Maifiah et al. 2016; Mishra et al. 2012). The unique structure of the membrane in GN bacteria is the primary reason for their rapid resistance development compared to GP bacteria (Breijyeh et al. 2020; Ghai and Ghai 2018). The lipid asymmetry, rigidity, and biochemistry of the LPS molecules in the membrane provide a considerable defensive barrier against numerous antibiotics (Breijyeh et al. 2020; Delcour 2009; Vasoo et al. 2015). Changes in the lipophilic composition and membrane structure can also influence various membrane-associated processes such as protein-lipid electrostatic interactions, ligand-binding, cell-to-cell communication, transport, and protein folding, translocation, and function (Corradi et al. 2019; Collinson 2019; Lin and Weibel 2016; Martens et al. 2019, 2016; Norimatsu et al. 2017; Du et al. 2018).
The bacterial lipid membrane is a viable target for novel antibiotic treatments as the lipophilic composition is crucial to antibiotic efficacy, and targeting the lipid membrane rather than biochemical pathways can prolong antibiotic resistance development (Dias and Rauter 2019; Lam et al. 2016). A better understanding of the bacterial lipid membrane and its interactions with antibiotics is thus imperative for subsequent antibiotic research and development efforts.
However, systematic studies of the bacterial cell membrane structure and its processes are difficult to perform when studying live bacterial cells due to the nanometre dimensions of their membranes as well as their high level of complexity (Behuria et al. 2020). Bacteria also possess a cell wall that requires removal prior to investigating membrane-mediated activities (Brown et al. 2010; Veron et al. 2008). The inherent complexity of biological bacterial cell membranes which contain numerous peptides, sugars, membrane proteins, lipids, and carbohydrates makes systematic investigations difficult (Andersson et al. 2018a; Castellana and Cremer 2006). Pathogenic bacteria especially pose unique investigatory challenges due to rigorous biosafety protocols (Behuria et al. 2020). An alternate method to analyse membrane-associated processes is to purify the bacterial membrane; however, the isolation process requires expensive instrumentation which is difficult to perform in common laboratories (Qing et al. 2019). Due to these limitations, progressions in the understanding of the organisation, structure, and processes that occur in biological bacterial membranes have been driven primarily through research on in vitro model membrane systems (Strahl and Errington 2017).
A variety of different model systems have been designed to mimic biological membranes in a controlled environment with only the most essential components (Salehi-Reyhani et al. 2017). Model membranes were developed as an accessible experimental platform to analyse membrane structure and function in an environment that replicates the fundamental environmental and physiochemical properties of biological membranes, whilst reducing their innate complexity (Andersson et al. 2018a, 2020, 2018b; Andersson and Köper 2016; Chan and Boxer 2007; Jackman et al. 2012; Siontorou et al. 2017). Model membrane systems are computationally modelled, free-standing, or solid-supported bilayer structures composed of various lipophilic compounds and proteins (Chan and Boxer 2007; Siontorou et al. 2017).
They enable the use of numerous microscopic, spectroscopic, electrochemical, reflectometric, and algorithmic analytical techniques often inaccessible when studying live cells (Wiebalck et al. 2016; Zieleniecki et al. 2016). The analytical techniques can, for example, reveal the mechanism of action surrounding membrane-targeting antibiotics (Peetla et al. 2009; Knobloch et al. 2015). Numerous model membrane systems have been designed to investigate membrane-drug interactions (Hollmann et al. 2018); however, few mimic bacterial membranes or the architecture of the ESKAPE pathogens.
Here, we provide an overview of the structure and lipophilic composition of GN and GP bacterial membranes and current membrane modelling systems for these structures, including liposomes, solid-supported bilayers, and computational simulations.
Bacterial membranes
Lipids in bacterial membranes serve as important structural and functional constituents and have important roles in membrane organisation, cell recognition, membrane fluidity, energy storage, direct modulation, membrane stability, cell signalling, and membrane formation (Solntceva et al. 2020; Carvalho and Caramujo 2018; Willdigg and Helmann 2021). To perform such complex and diverse functions, bacterial membranes are composed of approximately equivalent proportions of lipids and proteins and are complex structures with a high degree of organisation and variation between bacterial species and their GN and GP classifications (Strahl and Errington 2017; Epand and Epand 2009a; Sohlenkamp and Geiger 2016).
GN and GP bacterial lipid membranes are predominantly formed by phospholipids which are composed of a phosphate group, 2–4 hydrophobic fatty acid units, a variable hydrophilic head group, and a glycerol moiety (Sohlenkamp and Geiger 2016; Alagumuthu et al. 2019; Fahy et al. 2011). Phospholipids are organised in a classical bilayer described by the fluid-mosaic model (Singer and Nicolson 1972). The model has since been refined to accommodate the presence of lipid domains and cytoskeletal proteins that restrict and sectionalise lipid and protein diffusion (Strahl and Errington 2017; Meer et al. 2008; Barák and Muchová 2013). Both GN and GP bacteria contain a large variety of straight or branched, saturated, or unsaturated carboxylic acids with long aliphatic chains, known as fatty acids, that serve as essential building blocks for multiple lipophilic compounds (Carvalho and Caramujo 2018; Cronan and Thomas 2009). Numerous glycolipids, which are composed of a carbohydrate attached by a glycosidic bond containing 1–2 fatty acid units, are also typical constituents in the membranes of GN and GP bacteria (Bertani and Ruiz 2018; Reichmann and Gründling 2011). In addition to the aforementioned common lipid species, bacteria can also possess species-specific lipids (Solntceva et al. 2020).
Within bacterial species of different and the same Gram types, the lipid membrane contains a high degree of structural, chemical, and functional variability whereby numerous lipid molecular variants are present that differ in size, number, chemical composition, and isomeric form (Strahl and Errington 2017; Sohlenkamp and Geiger 2016; May and Grabowicz 2018; Rahman et al. 2000). Pathogens can also readily acquire multiple exogenous lipophilic bodies which generate substantial variation between pathogen strains and species (Jiang et al. 2019a; Jasim et al. 2018). The key lipid species present in the ESKAPE pathogens has been studied extensively (Table 1) (Sohlenkamp and Geiger 2016).
GN bacterial membranes consist of two lipid bilayers separated by a viscous, protein-enriched aqueous periplasmic space and a thin peptidoglycan (murein) wall (Fig. 1) (Kapoor et al. 2017; Barák and Muchová 2013; Silhavy et al. 2010). The inner membrane (IM) is comprised of an asymmetric phospholipid bilayer that encases the cytosol and harbours membrane proteins responsible for transport, energy production, protein secretion, and lipid biosynthesis (Silhavy et al. 2010; Bogdanov et al. 2020). The murein wall is responsible for protecting the bacterium against osmotic and mechanical stresses and maintaining bacterium shape (Kapoor et al. 2017; Silhavy et al. 2010). The outer membrane (OM) is attached to the murein wall via lipoproteins (Silhavy et al. 2010). The OM is an asymmetric lipid bilayer surrounding the periplasmic space (Kapoor et al. 2017; Paulowski et al. 2020). The proximal leaflet is comprised of phospholipids, whilst the distal leaflet is predominantly comprised of LPS which functions as a protective barrier (Silhavy et al. 2010; Cian et al. 2020). LPS is a glycolipid constructed of three distinct parts: lipid A (hydrophobic domain), the oligosaccharide core (hydrophilic domain), and the O-antigen (outmost polysaccharide domain) (Raetz and Whitfield 2002; Wang and Quinn 2010). The structure of LPS differs significantly between GN bacterial species due to survival adaptations in response to changes in environmental stimuli including pH, temperature, specific ion concentrations, osmolality, and toxins (including antibiotics) (Li et al. 2012; Needham and Trent 2013; Trent et al. 2006; Simpson and Trent 2019). Biochemical modifications to LPS domains or selective LPS production abandonment (specific to A. baumannii only) have been found to allow GN bacterial pathogens to evade host-immune attack, increase pathogenesis, and develop antimicrobial resistance (Needham and Trent 2013; Trent et al. 2006; Simpson and Trent 2019; Maldonado et al. 2016; Moffatt et al. 2010; Pelletier et al. 2013), for example, LPS modification adaptation strategies adopted by GN bacteria to protect themselves from cationic antimicrobials such as polymyxins include hydroxylation, dephosphorylation, palmitoylation, phosphatidylethanolamine addition, and 4-amino-4-deoxy-L-arabinose (L-Ara4N) addition to the lipid A portion (Dortet et al. 2020; Olaitan et al. 2014). The most common and effective modification to LPS in GN bacterial pathogens is the addition of L-Ara4N via cationic substitution of the 4’-phosphate group on the lipid A moiety (Olaitan et al. 2014; Nikaido 2003). This modification reduces the net charge of lipid A which, consequently, decreases the degree of electrostatic repulsion experienced between neighbouring LPS molecules. The incorporation of these cationic constituents results in a net positive charge of LPS upon biosynthesis which, inevitably, repulses cationic antimicrobials (Dortet et al. 2020; Olaitan et al. 2014). This repulsion results in antimicrobial resistance as the membrane has developed protection against OM disruption. In addition, murein lipoproteins and β-barrel proteins are present in the OM for murein wall anchoring and small (anions, maltodextrins, and maltose) and large molecule (antibiotics, vitamins and chelates) diffusion or transport (Silhavy et al. 2010).
The OM and LPS leaflets are absent in most GP bacteria which, in GN bacteria, are crucial in providing an additional stabilising layer around the bacterium and protect the bacterium from environmental hazards (Malanovic and Lohner 2016; Silhavy et al. 2010). To compensate for the OM deficit and withstand the osmotic and mechanical pressures exerted on the plasma membrane, GP bacteria are surrounded by a murein wall that is notably thicker (40–80 nm) in GP bacteria than those found in GN bacteria (7–8 nm) (Kapoor et al. 2017; Epand and Epand 2009a; Barák and Muchová 2013; Malanovic and Lohner 2016; Silhavy et al. 2010). Teichoic acids, including LTA, thread through the murein layers to anchor the murein wall to the membrane and regulate cell envelope function and structure (Malanovic and Lohner 2016; Silhavy et al. 2010). LTA is an alditol phosphate polymer linked by a glycolipid anchor that secures it to the lipid membrane (Solntceva et al. 2020; Percy and Gründling 2014). The structure of LTA varies significantly between GP bacterial species whereby there are five types of LTA (types I–V) that differ in core structure and glycolipid anchor (Percy and Gründling 2014; Shiraishi et al. 2013). Similarly to LPS in GN bacteria, biochemical modifications to the LTA backbone structure have been found to illicit antimicrobial resistance in GP bacterial pathogens (Percy and Gründling 2014; Gutmann et al. 1996; Saar-Dover et al. 2012). For example, the D-alanylation of LTA mediated by the dlt operon and/or incorporation of L-lysine in PG via the mprF gene can lead to an enhanced resistance against cationic antimicrobials (Percy and Gründling 2014; Saar-Dover et al. 2012; Abachin et al. 2002; Peschel et al. 1999; Reichmann et al. 2013). The modification increases the overall net positive surface charge of the membrane and reduces the binding affinity of cationic antimicrobials (Percy and Gründling 2014; Abachin et al. 2002; Peschel et al. 1999). However, other pathways may also be involved in resistance development. The addition of D-alanine, for example, also changes the conformation of LTA resulting in an increase in cell wall density and cell surface rigidity (Percy and Gründling 2014; Saar-Dover et al. 2012). This leads then to a reduction in the permeation of cationic antimicrobials through the cell. The membranes of GP bacteria are comprised of a single asymmetric phospholipid bilayer that encases the cytosol (Silhavy et al. 2010; Rosado et al. 2015; Jones et al. 2008). As there is no OM in GP bacteria to harbour extracellular proteins, GP bacteria are decorated with numerous proteins bound via peptide anchors, covalent interactions, lipid anchors, or non-covalent interactions to the membrane, murein wall, and/or teichoic acids that perform functions analogous to those found in GN bacteria (Malanovic and Lohner 2016; Silhavy et al. 2010; Scott and Barnett 2006).
Model membrane systems
Various model membrane systems have been established. Here, we focus on systems that specifically mimic microbial membranes.
Liposomes
Liposomes are spherical-shaped vesicles ranging from nano- to micrometre diameters that are comprised of one or more phospholipid bilayers that encase an aqueous core (Siontorou et al. 2017; Akbarzadeh et al. 2013). Liposome structures are categorised according to their lamellar structure and vesicular size: unilamellar vesicles (ULV) can be small (SUV, 0.02–0.04 µm), medium (MUV, 0.04–0.08 µm), large (LUV, 0.1–1 µm), and giant (GUV, > 1 µm) (Siontorou et al. 2017; Akbarzadeh et al. 2013; Šturm and Poklar Ulrih 2021). Oligolamellar vesicles (OLV) are > 0.5 µm and can contain 2–5 concentrically arranged bilayers, multilamellar vesicles (MLV) are > 0.7 µm and can contain concentrically arranged 5–25 bilayers, and multivesicular vesicles (MVV) are 1–100 µm and can contain one or more non-concentrically arranged internal bilayers (Fig. 2) (Akbarzadeh et al. 2013; Navas et al. 2005; Giuliano et al. 2021; Mu et al. 2018). Liposomes are easily formed via numerous methods as reviewed elsewhere (Siontorou et al. 2017; Akbarzadeh et al. 2013; Šturm and Poklar Ulrih 2021). Liposome properties can differ depending on the method of preparation, size, lipophilic composition, surface charge, and functionalisation which allows for a considerable degree of customisation (Gabizon et al. 1998; Sherratt and Mason 2018; Fan et al. 2007; Bozzuto and Molinari 2015; Riaz et al. 2018; Sakai-Kato et al. 2019).
Liposomes have been constructed to mimic the OM, IM, and cytoplasmic space of various non-pathogenic and pathogenic bacteria (Table 2) (Behuria et al. 2020; Bogdanov et al. 2020; Paulowski et al. 2020; Tuerkova et al. 2020; Dombach et al. 2020; Jamasbi et al. 2014; Kumagai et al. 2019; Pérez-Peinado et al. 2018; Malishev et al. 2018; Kahveci et al. 2016; Lopes et al. 2012; Cheng et al. 2011; Marín-Menéndez et al. 2017; Fernandez et al. 2011; Domenech et al. 2009; Pinheiro et al. 2013; D’Errico et al. 2010; Furusato et al. 2018; Kiss et al. 2021; Jiménez et al. 2011; Sikder et al. 2019; Kubiak et al. 2011; Mohanan et al. 2020; Ruhr and Sahl 1985; Bharatiya et al. 2021).
Often GUVs or LUVs are used that contain either bacterial lipid extracts (> 4 lipid species), or synthetic lipids determined by the user (< 3 lipid species) asymmetrically arranged in a bilayer. Liposome formation using bacterial lipid extracts provide a more biologically attune system as various lipid species and their native molecular variants are inherently incorporated. Under an artificially user-defined composition, the inner and outer leaflets for GP liposome models commonly contain PG, lysyl-PG, and CL, whilst GN liposome models commonly contain PE, PG, and CL and uncommonly LPS. Liposome models have been utilised to investigate basic structural (lipid domain architecture, rigidity, diffusion, and lateral organisation) and rheological (constriction, shrinkage, and invagination) membrane properties. In addition, protein and peptide-lipid interactions (Saliba et al. 2014; Su et al. 2011), lipid composition-dependent uptake, release, and molecule function (i.e. membrane-targeting antibiotics) (Kilelee et al. 2010; Som and Tew 2008; Brian Chia et al. 2011), pore formation (Samuel and Gillmor 2016; Sborgi et al. 2016), and protein activity (Carrasco-López et al. 2011; Sasaki et al. 2019) have been explored.
Liposome models have been developed for the ESKAPE pathogens and have been used to investigate host–pathogen interactions, membrane permeability, and the effect of membrane composition on antimicrobial susceptibility (Turner et al. 2015; Cheng et al. 2014; Lombardi et al. 2017; Zhang et al. 2014; Hancock and Nikaido 1978; Ciesielski et al. 2013; Lee et al. 1992; Mitchell et al. 2016). Liposomes from synthetic PC and PG lipids and S. aureus lipid extracts were used to determine the effects of lipid acyl chain branching on antimicrobial peptide activity (Mitchell et al. 2016). This was achieved by measuring efflux kinetics of the encapsulated fluorescent dye carboxyfluorescein, mediated by the model peptide δ-lysin. Liposomes composed of anteiso-branched isomers were less susceptible to peptide-induced perturbations than liposomes containing iso-branched isomers. In addition, liposomes made from S. aureus extracts were more resistant to peptide-induced perturbation than liposomes composed of synthetic lipids, most likely due to the additional increased fraction of anteiso-branched fatty acids.
In a different approach, the association of LPS extracted from K. pneumoniae with eukaryotic lipids has been investigated with respect to host immunodetection strategies (Ciesielski et al. 2013). This was achieved by analysing liposome-liposome interactions between pathogen membrane model liposomes containing LPS and PC and host membrane model liposomes containing PC, SL, and cholesterol. LPS preferentially segregated in ordered SL/cholesterol rich domains which was linked to the evolutionary drive for eukaryotic cells to generate, within such domains, a sensory protein for bacterial detection. The permeability of various carbapenems via porins in proteoliposomes reconstituted from lipids extracted from the OM of susceptible and resistant strains E. cloacae has also been studied (Lee et al. 1992). Carbapenem permeability and efficacy was highly dependent on the lipophilic constitution of the OM and the amount and type of porins present.
While liposomes are very useful systems to study, they pose some challenges for detailed biophysical studies. Lipid composition is often difficult to control (Rideau et al. 2018; Weinberger et al. 2013). Methods to enhance compositional complexity have been developed (Göpfrich et al. 2019; Pautot et al. 2003); however, they can inhibit surface property analysis (Rideau et al. 2018). The metastable structure of liposomes and their susceptibility to lipophilic, oxidative, and hydrolytic degradation offers poor long-term stability (Akbarzadeh et al. 2013; Nkanga et al. 2019). Additionally, lipids often have relatively high phase transition temperatures which impede liposome formation (Eeman and Deleu 2010; Vestergaard et al, 2008). Finally, despite existing stabilisation methods (Schmid et al. 2015), protein reconstitution in liposomes still remains a challenge (Chan and Boxer 2007; Siontorou et al. 2017).
Solid-supported bilayers:
Solid-supported bilayer lipid membranes (sBLMs) consist of a lipid bilayer that is placed onto a solid substrate either via direct contact, via separation by a polymer cushion, or allowed to float directly above a covalently-bound self-assembled monolayer or a supported bilayer (Fig. 3) (Andersson and Köper 2016; Belegrinou et al. 2011; Sackmann 1996; Foglia et al. 2015). Tethered bilayer lipid membranes (tBLMs) are sBLMs with the proximal bilayer leaflet covalently linked to the substrate though thiolipid, oligopeptide, alkane- and aromatic-thiol, polymer, or protein anchors (Andersson and Köper 2016; Andersson et al. 2018b; Jackman et al. 2012; Li et al. 2015; Köper 2007). sBLMs and tBLMs have good electrical sealing properties, are air-stable, and can be formed via Langmuir transfer, vesicle fusion, or solvent-exchange techniques (Andersson et al. 2020; Jackman et al. 2012; Girard-Egrot and Maniti 2021; Kurniawan et al. 2018; Richter et al. 2003).
Gold is the most commonly utilised substrate material for sBLMs and tBLMs due to its stability, facile functionalisation, and versatility in surface analysis techniques (Andersson and Köper 2016). However, other substrates including mercury, quartz, glass, aluminium oxide, indium tin oxide, silicon oxide, sapphire, mica, silver, and titanium oxide can also be utilised (Andersson et al. 2018b; Girard-Egrot and Maniti 2021; Clifton et al. 2020; Giess et al. 2004).
Surface sensitive techniques such as surface plasmon resonance, ellipsometry, neutron or X-ray reflectometry, atomic force microscopy, electrochemical impedance spectroscopy, quartz crystal microbalance with dissipation monitoring, and infrared reflection absorption spectroscopy are well-suited methods of surface analysis for these planar systems in aqueous solution (Ferhan et al. 2017; Wittenberg et al. 2014; Steltenkamp et al. 2006).
While these membrane systems commonly have simple lipid compositions, increased biological accuracy can be achieved in both sBLMs and tBLMs by customising the lipid composition to change membrane electrical sealing and structural properties (Andersson and Köper 2016; Andersson et al. 2018b; Girard-Egrot and Maniti 2021). tBLMs can also change the aforementioned membrane properties and facilitate protein incorporation by customising the tethering type, composition, and density. The OM and IM of various non-pathogenic and pathogenic bacteria have been modelled using both tBLMs and sBLMs (Table 3) (Paulowski et al. 2020; Pérez-Peinado et al. 2018; Weiss et al. 2010; Clifton et al. 2013; Paracini et al. 2018; Hughes et al. 2019; Dodd et al. 2008; Michel et al. 2017; Adhyapak et al. 2020; Nakatani et al. 2019; Hoiles and Krishnamurthy 2015; Schneck et al. 2009; Lee et al. 2020; Nedelkovski et al. 2013; Niu et al. 2017; Sharma et al. 2020; McGillivray et al. 2009).
These architectures often contain a limited number (1–4) of synthetic lipid species; however, they can also contain bacterial lipid extracts (> 4 lipid species) asymmetrically arranged in a bilayer. Unlike user-defined systems which are limited to the number and type of lipid species and their associated molecular variations incorporated, architectures formed from bacterial lipid extracts generate increasingly accurate biological models as various lipid species and their native molecular variants are inherently incorporated. Under user-defined compositions, the inner and outer leaflets of architectures modelling GN and GP bacteria commonly contain one molecular variation of PC. Few architectures have been developed where the inner and outer leaflets contain the most common lipid species or analogues thereof for GN (PE, PG and CL) and GP (PG, CL, and lysyl-PG) bacteria. For sBLM and tBLM systems, lysyl-PG is often substituted with DOTAP as it is more affordable for the increased quantities required to generate the architectures (Dupuy et al. 2018; Li and Smith 2019). Few architectures modelling the membrane of GN or GP bacteria have also been developed to contain LPS (Andersson et al. 2018a; Clifton et al. 2015; Hsia et al. 2016; Thomas et al. 1999) or murein (Spencelayh et al. 2006). The model architectures have been utilised to investigate general structural (thickness, roughness, and lipid density) and electrical membrane properties. In addition, the mechanism of interaction between antibiotic compounds and membrane constituents (Chilambi et al. 2018; Dupuy et al. 2018; Li and Smith 2019), lipid-protein interactions (Mirandela et al. 2019), ion transport (Maccarini et al. 2017), and redox-active enzyme function and characterisation (Jeuken et al. 2006, 2005) have been explored.
Limited architectures have been generated to model the ESKAPE pathogens and investigate electrochemical and structural changes with lipophilic composition (Jiang et al. 2019b; Mohamed et al. 2021; Zang et al. 2021). Recently, a tBLM for A. baumannii has been developed to model the OM in the presence and absence of exogenously incorporated omega-3 polyunsaturated fatty acid (PUFA) and docosahexaenoic acid (DHA) (Zang et al. 2021). Both tBLMs generated were asymmetrical and were constructed from lipid samples extracted from A. baumannii actively growing in the presence or absence of DHA. The tBLMs were used to determine whether DHA incorporation disrupted the function of efflux system AdeB due to impaired proton motive force retention from induced ion leakage. Both tBLM models were electrochemically similar therefore suggesting that AdeB dysfunction was not due to the membrane’s ability to maintain a proton motive force upon DHA incorporation. sBLM models for S. aureus have been developed to assess how upregulation in CL biosynthesis in daptomycin-resistant strains decreases antibiotic susceptibility (Jiang et al. 2019b). PG, lysyl-PG and CL in different concentration ratios were used to mimic resistant and susceptible strains. The daptomycin-resistant strain membrane was found to be thicker than the susceptible strain. The structural changes resulted in concentration-dependent changes in daptomycin interaction. At low daptomycin concentrations, the susceptible strain exhibited decreases in lipid volume whilst high concentrations induced considerable membrane penetration and disruption. In contrast, the resistant-strain exhibited only slight lipid volume reductions for all daptomycin concentrations analysed. This demonstrated that lipid-induced structural modifications can impair daptomycin efficacy.
Both sBLM and tBLM systems possess limitations unique to each architecture. sBLM systems can be unstable due to no linkage between the lipid bilayer and the substrate (Andersson and Köper 2016; Andersson et al. 2018b; Girard-Egrot and Maniti 2021). As a result, measurements requiring days or weeks are difficult to achieve. Direct bilayer-substrate contact can also create an insufficient amount of space for bilayer-spanning protein incorporation (Castellana and Cremer 2006; Andersson and Köper 2016; Alghalayini et al. 2019; Tamm and McConnell 1985). Protein-substrate contact induces denaturation or impaired function which hinders functional, electrical, or structural studies (Alghalayini et al. 2019; Tanaka and Sackmann 2005). Membrane structural and electrical properties are also subject to substrate topology, whereby any substrate imperfections will cause defects in the bilayer and hinder its resistance towards current transfer (Andersson and Köper 2016; Andersson et al. 2018b; Girard-Egrot and Maniti 2021). Using a polymer cushion to support the bilayer can partially reduce substrate topological effects, maintain bilayer fluidity, and prevent substrate-protein contact (Andersson and Köper 2016; Andersson et al. 2018b; Belegrinou et al. 2011). However, polymer cushion swelling behaviour, assembly, thickness, and morphology are difficult to control which dampens the electrical qualities of the lipid bilayer (Naumann et al. 2001, 2002). tBLMs were generated to circumvent all aforementioned limitations of sBLMs. However, the disadvantage of increased stability and electrical sealing in tBLM systems is decreased lateral lipid mobility (Andersson et al. 2018b). Depending upon the application, there are also disadvantages to using different types of tethers (Jackman et al. 2012). Similarly to liposomes, consideration of the lipid phase transition temperature can be crucial to successful lipid incorporation and architecture formation (Eeman and Deleu 2010; Vestergaard and d., Hamada, T., Takagi, M., 2008).
Computational modelling
Despite the progress made in developing sophisticated experimental techniques that can directly investigate live bacterial cells and reveal complex lateral membrane organisation processes (Deleu et al. 2014; Lyman et al. 2018; Nickels et al. 2015), analysing the molecular details surrounding membrane organisation still proves difficult (Maity et al. 2015; Marrink et al. 2019). Molecular dynamics (MD) techniques can serve as a “computational microscope” whereby interactions between all constituents in the system can be analysed at an atomistic level (Marrink et al. 2019; Ingólfsson et al. 2016). The quality of the set of parameters that dictate particle interaction, known as the force field (FF), is crucial to the success of an MD simulation (MacKerell 2004). In biomolecular simulations, numerous FFs have been employed: implicit, supra-coarse-grain, coarse-grain, and all-atom (Marrink et al. 2019; Mori et al. 2016). All FFs are similar regarding their main approximations and function; however, the level of resolution between each is distinctive (Fig. 4) (MacKerell 2004). The highest level of resolution is full atomistic detail which is the most commonly utilised model for complex membrane systems. These include bacterial membranes, organelle membranes, plasma membranes and viral envelopes, protein folding, drug-membrane interactions, protein–ligand complex stability, protein–protein interaction modulators, lipid domain formation and behaviour, membrane curvature sensing and formation, membrane remodelling events, and lipid-protein binding site identification and binding strength (Matamoros-Recio et al. 2021; Bennett and Tieleman 2013; Chan et al. 2015; Kabedev et al. 2021; Khan et al. 2019; Lazim et al. 2020; Liu et al. 2021; Parkin et al. 2015; Reddy and Sansom 2016; Singharoy and Schulten 2017). Full atomistic detail significantly expands the predictive power of molecular dynamics simulations. To enhance the spatiotemporal range of MD simulations and decrease system complexity, the lower resolution level FFs can be utilised (Mori et al. 2016; Liu et al. 2021).
Several MD models simulating the OM and IM of bacteria have been constructed at both the atomistic and coarse-grained levels of resolution (Table 4). (Bogdanov et al. 2020; Tuerkova et al. 2020; Hughes et al. 2019; Balusek and Gumbart 2016; Baltoumas et al. 2019; Gao et al. 2020; Kholina et al. 2020; Li and Guo 2013; Abellón-Ruiz et al. 2017; Berglund et al. 2015; Hsu et al. 2017a, 2017b; Ma et al. 2017a, 2017b, 2015; Mehmood et al. 2016; Orekhov et al. 2018; Shearer et al. 2019; Shearer and Khalid 2018; Rice and Wereszczynski 2018; Patel et al. 2016; Piggot et al. 2011; Carpenter et al. 2016; Fleming et al. 2016; Wu et al. 2013, 2014a; Duay et al. 2019; Khondker et al. 2019; Pandit and Klauda 2012; Pothula et al. 2016; Shahane et al. 2019).
These models often contain 2 or more different lipid species asymmetrically arranged in a bilayer, with the outer and inner leaflets composed primarily of LPS (restricted to the outer leaflet) and/or a mixture of PE, PG and sometimes CL. To compensate for the significant variation in the constituents of the phospholipids and LPS between bacterial strains and species, a range of different phospholipid and LPS fragments and variants have been parametrised for use in MD programs (Lee et al. 2018; Wu et al. 2014b). The models have been utilised to characterise and explore various membrane channels and bacterial membrane properties including divalent cation binding, density, diffusion, packing, rigidity, and average area per lipid. In addition, lipid changes between bacterial growth cycles (Khakbaz and Klauda 2015; Lim and Klauda 2011), effects of mechanical and oxidative stressors (Hwang et al. 2018), molecule permeation and partitioning (Jin et al. 2021; Hsu et al. 2016), and the lipophilic influence on membrane protein function and packing (Khalid et al. 2015; Patel et al. 2017) have also been explored.
Bacterial membranes modelling the ESKAPE pathogens have also been simulated to investigate drug-membrane interactions, lipid-protein interactions, and structural changes associated with bacterial pathogenesis (Zang et al. 2021; Piggot et al. 2011; Lee et al. 2017; Ocampo-Ibáñez et al. 2020; Alkhalifa et al. 2020; Lins and Straatsma 2001; Yu and Klauda 2018; Kirschner et al. 2012; Dias et al. 2014; Oosten and Harroun 2016; Chakraborty et al. 2020; Kim et al. 2016). Models for A. baumannii containing the OM/IM spanning AdeB RND drug-efflux complex in the presence and absence of incorporated host-derived PUFAs, arachidonic acid, and DHA have been developed within the coarse-grained FF to investigate PUFA-mediated antibiotic susceptibility (Zang et al. 2021). All three simulated membranes were asymmetrical, contained three different lipid species notably PG, CL, and PE and 2–7 molecular variations of each. PUFA incorporation was shown to morphologically disrupt AdeB, resulting in impaired efflux function and presented a potential weakness in A. baumannii’s MDR capacity. Chakraborty et al. (2020) also explored various drug-membrane-dependent interactions of two antimicrobial peptides, battacin analogues octapeptide 17 and pentapeptide 30, with the IM of S. aureus using an atomistic FF (Chakraborty et al. 2020). The IM was an asymmetric three-component mixture predominately of PG, lysine-PG, DPG, and CL. Kim et al. (2016) modelled homogenous bilayers from 12 pathogenic bacterial species, including A. baumannii, K. pneumoniae, and P. aeruginosa, using an atomistic FF to investigate atomistic-scale similarities and differences in membrane properties induced by the structural variations in LPS (Kim et al. 2016).
Molecular dynamic simulations can provide a detailed picture of membrane structure, yet they sometimes limited by the high complexity of biological membrane systems. For comprehensive reviews of the analytical limitations of MD simulations, see Marrink et al. (2019) (Marrink et al. 2019) and Goossens and Winter (2018). (Goossens and Winter 2018) Developments in the field are however very promising.
Outlook
The membrane models used to mimic pathogenic bacterial membranes and the techniques used to analyse them have provided useful information on the lateral organisation of these adaptable quasi two-dimensional architectures during resistance development. Each architecture possesses individual advantages and limitations when investigating drug-membrane interactions, lipid-protein interactions, host–pathogen interactions, and structure-induced bacterial pathogenesis. As in vitro modelling systems advance, the quest for increased realism has not ceased. Key challenges include observing and incorporating complex membrane proteins such as drug-efflux proteins, connecting theoretical and experimental results, and incorporating more complex lipophilic assemblies. Current model systems are created utilising well-defined lipid mixtures, and whilst simplification is necessary for specific membrane-mediated interaction analyses, oversimplification provides an insufficient understanding of complex bacterial membrane systems and processes. By incorporating more complex compositions (proteins and lipids), insights into essential pathogen resistance development processes, membrane-targeting antimicrobial mechanisms, and generating fully artificial architectures that safely captures numerous essential pathogenic biological features can be made to help combat the devastating consequences of antibiotic resistance.
References
Watson H (2015) Biological membranes. Essays Biochem 59:43–69. https://doi.org/10.1042/bse0590043
Guidotti G (1972) The composition of biological membranes. Arch Intern Med 129(2):194–201. https://doi.org/10.1001/archinte.1972.00320020038003
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48(1):1–12. https://doi.org/10.1086/595011
Del Mar CB, Scott AM, Glasziou PP, Hoffmann T, van Driel ML, Beller E, Phillips SM, Dartnell J (2017) Reducing antibiotic prescribing in Australian general practice: time for a national strategy. Med J Aust 207(9):401–406. https://doi.org/10.5694/mja17.00574
Pendleton JN, Gorman SP, Gilmore BF (2013) Clinical relevance of the ESKAPE pathogens. Expert Rev Anti Infect Ther 11(3):297–308. https://doi.org/10.1586/eri.13.12
Rice LB (2010) Progress and challenges in implementing the research on ESKAPE pathogens. Infect Control Hosp Epidemiol 31(S1):S7–S10. https://doi.org/10.1086/655995
Santajit, S.; Indrawattana, N., Mechanisms of antimicrobial resistance in ESKAPE pathogens. BioMed research international 2016, 2016. https://doi.org/10.1155/2016/2475067
Ventola CL (2015) The antibiotic resistance crisis: part 1: causes and threats. Pharmacy and Therapeutics 40(4):277
Chilambi GS, Gao IH, Yoon BK, Park S, Kawakami LM, Ravikumar V, Chan-Park MB, Cho N-J, Bazan GC, Kline KA (2018) Membrane adaptation limitations in Enterococcus faecalis underlie sensitivity and the inability to develop significant resistance to conjugated oligoelectrolytes. RSC Adv 8(19):10284–10293. https://doi.org/10.1039/C7RA11823F
Gould IM, Bal AM (2013) New antibiotic agents in the pipeline and how they can help overcome microbial resistance. Virulence 4(2):185–191. https://doi.org/10.4161/viru.22507
Fernández L, Hancock RE (2012) Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev 25(4):661–681. https://doi.org/10.1128/cmr.00043-12
Prestinaci F, Pezzotti P, Pantosti A (2015) Antimicrobial resistance: a global multifaceted phenomenon. Pathogens and Global Health 109(7):309–318. https://doi.org/10.1179/2047773215Y.0000000030
Jiang, J.-H.; Hassan, K. A.; Begg, S. L.; Rupasinghe, T. W.; Naidu, V.; Pederick, V. G.; Khorvash, M.; Whittall, J. J.; Paton, J. C.; Paulsen, I. T., Identification of novel Acinetobacter baumannii host fatty acid stress adaptation strategies. Mbio 2019, 10 (1). https://doi.org/10.1128/mBio.02056-18
Renwick, M. J.; Simpkin, V.; Mossialos, E.; Organization, W. H., Targeting innovation in antibiotic drug discovery and development: The need for a One Health–One Europe–One World Framework. World Health Organization. Regional Office for Europe: 2016
Dutescu IA, Hillier SA (2021) Encouraging the Development of New Antibiotics: Are Financial Incentives the Right Way Forward? A Systematic Review and Case Study. Infect Drug Resist 14:415. https://doi.org/10.2147/IDR.S287792
D’Andrea, M. M.; Fraziano, M.; Thaller, M. C.; Rossolini, G. M., The urgent need for novel antimicrobial agents and strategies to fight antibiotic resistance. Multidisciplinary Digital Publishing Institute: 2019. https://doi.org/10.3390/antibiotics8040254
Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, Pulcini C, Kahlmeter G, Kluytmans J, Carmeli Y (2018) Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18(3):318–327. https://doi.org/10.1016/s1473-3099(17)30753-3
Mulani MS, Kamble EE, Kumkar SN, Tawre MS, Pardesi KR (2019) Emerging strategies to combat ESKAPE pathogens in the era of antimicrobial resistance: a review. Front Microbiol 10:539. https://doi.org/10.3389/fmicb.2019.00539
Makabenta JMV, Nabawy A, Li C-H, Schmidt-Malan S, Patel R, Rotello VM (2021) Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections. Nat Rev Microbiol 19(1):23–36. https://doi.org/10.1038/s41579-020-0420-1
Fatima F, Siddiqui S, Khan WA (2021) Nanoparticles as novel emerging therapeutic antibacterial agents in the antibiotics resistant era. Biol Trace Elem Res 199(7):2552–2564. https://doi.org/10.1007/s12011-020-02394-3
Mantravadi PK, Kalesh KA, Dobson RC, Hudson AO, Parthasarathy A (2019) The quest for novel antimicrobial compounds: emerging trends in research, development, and technologies. Antibiotics 8(1):8. https://doi.org/10.3390/antibiotics8010008
Charbonneau MR, Isabella VM, Li N, Kurtz CB (2020) Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat Commun 11(1):1–11. https://doi.org/10.1038/s41467-020-15508-1
Hussein M, Karas JA, Schneider-Futschik EK, Chen F, Swarbrick J, Paulin OK, Hoyer D, Baker M, Zhu Y, Li J (2020) The killing mechanism of teixobactin against methicillin-resistant Staphylococcus aureus: an untargeted metabolomics study. Msystems 5(3):e00077-e120. https://doi.org/10.1128/mSystems.00077-20
Hutchings MI, Truman AW, Wilkinson B (2019) Antibiotics: past, present and future. Curr Opin Microbiol 51:72–80. https://doi.org/10.1016/j.mib.2019.10.008
Quinto EJ, Caro I, Villalobos-Delgado LH, Mateo J, De-Mateo-Silleras B, Redondo-Del-Río MP (2019) Food Safety through Natural Antimicrobials. Antibiotics 8(4):208. https://doi.org/10.3390/antibiotics8040208
Ghrairi, T.; Jaraud, S.; Alves, A.; Fleury, Y.; El Salabi, A.; Chouchani, C., New insights into and updates on antimicrobial agents from natural products. Hindawi: 2019. https://doi.org/10.1155/2019/7079864
Kapoor G, Saigal S, Elongavan A (2017) Action and resistance mechanisms of antibiotics: A guide for clinicians. J Anaesthesiol Clin Pharmacol 33(3):300. https://doi.org/10.4103/joacp.JOACP_349_15
Epand RM, Walker C, Epand RF, Magarvey NA (2016) Molecular mechanisms of membrane targeting antibiotics. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858(5):980–987. https://doi.org/10.1016/j.bbamem.2015.10.018
Tenover FC (2006) Mechanisms of antimicrobial resistance in bacteria. Am J Med 119(6):S3–S10. https://doi.org/10.1016/j.amjmed.2006.03.011
Dias C, Rauter AP (2019) Membrane-targeting antibiotics: recent developments outside the peptide space. Future Med Chem 11(3):211–228. https://doi.org/10.4155/fmc-2018-0254
Dadhich R, Kapoor S (2020) Various Facets of Pathogenic Lipids in Infectious Diseases: Exploring Virulent Lipid-Host Interactome and Their Druggability. J Membr Biol 253(5):399–423. https://doi.org/10.1007/s00232-020-00135-0
Han, M.-L.; Zhu, Y.; Creek, D. J.; Lin, Y.-W.; Anderson, D.; Shen, H.-H.; Tsuji, B.; Gutu, A. D.; Moskowitz, S. M.; Velkov, T., Alterations of metabolic and lipid profiles in polymyxin-resistant Pseudomonas aeruginosa. Antimicrobial agents and chemotherapy 2018, 62 (6). https://doi.org/10.1128/AAC.02656-17
Jiang J-H, Bhuiyan MS, Shen H-H, Cameron DR, Rupasinghe TW, Wu C-M, Le Brun AP, Kostoulias X, Domene C, Fulcher AJ (2019b) Antibiotic resistance and host immune evasion in Staphylococcus aureus mediated by a metabolic adaptation. Proc Natl Acad Sci 116(9):3722–3727. https://doi.org/10.1073/pnas.1812066116
Maifiah MHM, Cheah S-E, Johnson MD, Han M-L, Boyce JD, Thamlikitkul V, Forrest A, Kaye KS, Hertzog P, Purcell AW (2016) Global metabolic analyses identify key differences in metabolite levels between polymyxin-susceptible and polymyxin-resistant Acinetobacter baumannii. Sci Rep 6(1):1–17. https://doi.org/10.1038/srep22287
Mishra NN, Bayer AS, Tran TT, Shamoo Y, Mileykovskaya E, Dowhan W, Guan Z, Arias CA (2012) Daptomycin resistance in enterococci is associated with distinct alterations of cell membrane phospholipid content. PloS one 7(8):e43958. https://doi.org/10.1371/journal.pone.0043958
Breijyeh Z, Jubeh B, Karaman R (2020) Resistance of Gram-negative bacteria to current antibacterial agents and approaches to resolve it. Molecules 25(6):1340. https://doi.org/10.3390/molecules25061340
Ghai I, Ghai S (2018) Understanding antibiotic resistance via outer membrane permeability. Infect Drug Resist 11:523. https://doi.org/10.2147/idr.s156995
Delcour AH (2009) Outer membrane permeability and antibiotic resistance. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics 1794(5):808–816. https://doi.org/10.1016/j.bbapap.2008.11.005
Vasoo, S.; Barreto, J. N.; Tosh, P. K. In Emerging issues in gram-negative bacterial resistance: an update for the practicing clinician, Mayo Clinic Proceedings, Elsevier: 2015, 395–403. https://doi.org/10.1016/j.mayocp.2014.12.002
Corradi V, Sejdiu BI, Mesa-Galloso H, Abdizadeh H, Noskov SY, Marrink SJ, Tieleman DP (2019) Emerging diversity in lipid–protein interactions. Chem Rev 119(9):5775–5848. https://doi.org/10.1021/acs.chemrev.8b00451
Collinson I (2019) The dynamic ATP-Driven mechanism of bacterial protein translocation and the critical role of phospholipids. Front Microbiol 10:1217. https://doi.org/10.3389/fmicb.2019.01217
Lin T-Y, Weibel DB (2016) Organization and function of anionic phospholipids in bacteria. Appl Microbiol Biotechnol 100(10):4255–4267. https://doi.org/10.1007/s00253-016-7468-x
Martens C, Shekhar M, Lau AM, Tajkhorshid E, Politis A (2019) Integrating hydrogen–deuterium exchange mass spectrometry with molecular dynamics simulations to probe lipid-modulated conformational changes in membrane proteins. Nat Protoc 14(11):3183–3204. https://doi.org/10.1038/s41596-019-0219-6
Martens C, Stein RA, Masureel M, Roth A, Mishra S, Dawaliby R, Konijnenberg A, Sobott F, Govaerts C, Mchaourab HS (2016) Lipids modulate the conformational dynamics of a secondary multidrug transporter. Nat Struct Mol Biol 23(8):744. https://doi.org/10.1038/nsmb.3262
Norimatsu Y, Hasegawa K, Shimizu N, Toyoshima C (2017) Protein–phospholipid interplay revealed with crystals of a calcium pump. Nature 545(7653):193–198. https://doi.org/10.1038/nature22357
Du D, Wang-Kan X, Neuberger A, van Veen HW, Pos KM, Piddock LJ, Luisi BF (2018) Multidrug efflux pumps: structure, function and regulation. Nat Rev Microbiol 16(9):523–539. https://doi.org/10.1038/s41579-018-0048-6
Lam SJ, O’Brien-Simpson NM, Pantarat N, Sulistio A, Wong EH, Chen Y-Y, Lenzo JC, Holden JA, Blencowe A, Reynolds EC (2016) Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers. Nat Microbiol 1(11):1–11. https://doi.org/10.1038/nmicrobiol.2016.162
Behuria, H.; Pal, N.; Munda, R.; Sahu, S., Preparation of Giant Unilamellar Vesicles (GUVS) from Bacterial Polar Lipid Extract: Developing a Prokaryotic Model Membrane System. In Biotechnology for Sustainable Utilization of Bioresources, Astral International Pvt. Ltd: New Delhi, 2020, 309-320
Brown S, Meredith T, Swoboda J, Walker S (2010) Staphylococcus aureus and Bacillus subtilis W23 make polyribitol wall teichoic acids using different enzymatic pathways. Chem Biol 17(10):1101–1110. https://doi.org/10.1016/j.chembiol.2010.07.017
Veron W, Orange N, Feuilloley MG, Lesouhaitier O (2008) Natriuretic peptides modify Pseudomonas fluorescens cytotoxicity by regulating cyclic nucleotides and modifying LPS structure. BMC Microbiol 8(1):1–11. https://doi.org/10.1186/1471-2180-8-114
Andersson J, Fuller MA, Wood K, Holt SA, Köper I (2018a) A tethered bilayer lipid membrane that mimics microbial membranes. Phys Chem Chem Phys 20(18):12958–12969. https://doi.org/10.1039/C8CP01346B
Castellana ET, Cremer PS (2006) Solid supported lipid bilayers: From biophysical studies to sensor design. Surf Sci Rep 61(10):429–444. https://doi.org/10.1016/j.surfrep.2006.06.001
Qing G, Gong N, Chen X, Chen J, Zhang H, Wang Y, Wang R, Zhang S, Zhang Z, Zhao X (2019) Natural and engineered bacterial outer membrane vesicles. Biophysics Reports 5(4):184–198. https://doi.org/10.1007/s41048-019-00095-6
Strahl H, Errington J (2017) Bacterial membranes: structure, domains, and function. Annu Rev Microbiol 71:519–538. https://doi.org/10.1146/annurev-micro-102215-095630
Salehi-Reyhani A, Ces O, Elani Y (2017) Artificial cell mimics as simplified models for the study of cell biology. Exp Biol Med 242(13):1309–1317. https://doi.org/10.1177/1535370217711441
Andersson J, Bilotto P, Mears LL, Fossati S, Ramach U, Köper I, Valtiner M, Knoll W (2020) Solid-supported lipid bilayers–A versatile tool for the structural and functional characterization of membrane proteins. Methods 180:56–68. https://doi.org/10.1016/j.ymeth.2020.09.005
Andersson J, Köper I (2016) Tethered and polymer supported bilayer lipid membranes: structure and function. Membranes 6(2):30. https://doi.org/10.3390/membranes6020030
Andersson J, Köper I, Knoll W (2018b) Tethered membrane architectures—design and applications. Front Mater 5:55. https://doi.org/10.3389/fmats.2018.00055
Chan Y-HM, Boxer SG (2007) Model membrane systems and their applications. Curr Opin Chem Biol 11(6):581–587. https://doi.org/10.1016/j.cbpa.2007.09.020
Jackman JA, Knoll W, Cho N-J (2012) Biotechnology applications of tethered lipid bilayer membranes. Materials 5(12):2637–2657. https://doi.org/10.3390/ma5122637
Siontorou CG, Nikoleli G-P, Nikolelis DP, Karapetis SK (2017) Artificial lipid membranes: Past, present, and future. Membranes 7(3):38. https://doi.org/10.3390/membranes7030038
Wiebalck S, Kozuch J, Forbrig E, Tzschucke CC, Jeuken LJ, Hildebrandt P (2016) Monitoring the transmembrane proton gradient generated by cytochrome bo 3 in tethered bilayer lipid membranes using SEIRA spectroscopy. J Phys Chem B 120(9):2249–2256. https://doi.org/10.1021/acs.jpcb.6b01435
Zieleniecki JL, Nagarajan Y, Waters S, Rongala J, Thompson V, Hrmova M, Köper I (2016) Cell-free synthesis of a functional membrane transporter into a tethered bilayer lipid membrane. Langmuir 32(10):2445–2449. https://doi.org/10.1021/acs.langmuir.5b04059
Peetla C, Stine A, Labhasetwar V (2009) Biophysical interactions with model lipid membranes: applications in drug discovery and drug delivery. Mol Pharm 6(5):1264–1276. https://doi.org/10.1021/mp9000662
Knobloch J, Suhendro DK, Zieleniecki JL, Shapter JG, Köper I (2015) Membrane–drug interactions studied using model membrane systems. Saudi J Biol Sci 22(6):714–718. https://doi.org/10.1016/j.sjbs.2015.03.007
Hollmann A, Martinez M, Maturana P, Semorile LC, Maffia PC (2018) Antimicrobial peptides: interaction with model and biological membranes and synergism with chemical antibiotics. Front Chem 6:204. https://doi.org/10.3389/fchem.2018.00204
Solntceva V, Kostrzewa M, Larrouy-Maumus G (2020) Detection of species-specific lipids by routine MALDI TOF mass spectrometry to unlock the challenges of microbial identification and antimicrobial susceptibility testing. Front Cell Infect Microbiol 10:914. https://doi.org/10.3389/fcimb.2020.621452
De Carvalho CC, Caramujo MJ (2018) The various roles of fatty acids. Molecules 23(10):2583. https://doi.org/10.3390/molecules23102583
Willdigg JR, Helmann JD (2021) Mini Review: Bacterial Membrane Composition and Its Modulation in Response to Stress. Front Mol Biosci 8:338. https://doi.org/10.3389/fmolb.2021.634438
Epand RM, Epand RF (2009) Lipid domains in bacterial membranes and the action of antimicrobial agents. Biochimica et Biophysica Acta (BBA)-Biomembranes 1788(1):289–294. https://doi.org/10.1016/j.bbamem.2008.08.023
Sohlenkamp C, Geiger O (2016) Bacterial membrane lipids: diversity in structures and pathways. FEMS Microbiol Rev 40(1):133–159. https://doi.org/10.1093/femsre/fuv008
Alagumuthu M, Dahiya D, Nigam PS (2019) Phospholipid—the dynamic structure between living and non-living world; a much obligatory supramolecule for present and future [J]. AIMS Mol Sci 6(1):1–19. https://doi.org/10.3934/molsci.2019.1.1
Fahy E, Cotter D, Sud M, Subramaniam S (2011) Lipid classification, structures and tools. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1811(11):637–647. https://doi.org/10.1016/j.bbalip.2011.06.009
Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. Science 175(4023):720–731. https://doi.org/10.1126/science.175.4023.720
Van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9(2):112–124. https://doi.org/10.1038/nrm2330
Barák I, Muchová K (2013) The role of lipid domains in bacterial cell processes. Int J Mol Sci 14(2):4050–4065. https://doi.org/10.3390/ijms14024050
Cronan JE, Thomas J (2009) Bacterial fatty acid synthesis and its relationships with polyketide synthetic pathways. Methods Enzymol 459:395–433. https://doi.org/10.1016/s0076-6879(09)04617-5
Bertani, B.; Ruiz, N., Function and biogenesis of lipopolysaccharides. EcoSal Plus 2018, 8 (1). https://doi.org/10.1128/ecosalplus.esp-0001-2018
Reichmann NT, Gründling A (2011) Location, synthesis and function of glycolipids and polyglycerolphosphate lipoteichoic acid in Gram-positive bacteria of the phylum Firmicutes. FEMS Microbiol Lett 319(2):97–105. https://doi.org/10.1111/j.1574-6968.2011.02260.x
May KL, Grabowicz M (2018) The bacterial outer membrane is an evolving antibiotic barrier. Proc Natl Acad Sci 115(36):8852–8854. https://doi.org/10.1073/pnas.1812779115
Rahman MM, Kolli VK, Kahler CM, Shih G, Stephens DS, Carlson RW (2000) The membrane phospholipids of Neisseria meningitidis and Neisseria gonorrhoeae as characterized by fast atom bombardment mass spectrometry. Microbiology 146(8):1901–1911. https://doi.org/10.1099/00221287-146-8-1901
Jasim R, Han M-L, Zhu Y, Hu X, Hussein MH, Lin Y-W, Zhou QT, Dong CYD, Li J, Velkov T (2018) Lipidomic analysis of the outer membrane vesicles from paired polymyxin-susceptible and-resistant Klebsiella pneumoniae clinical isolates. Int J Mol Sci 19(8):2356. https://doi.org/10.3390/ijms19082356
Theilacker C, Kropec A, Hammer F, Sava I, Wobser D, Sakinc T, Codée JD, Hogendorf WF, van der Marel GA, Huebner J (2012) Protection against Staphylococcus aureus by antibody to the polyglycerolphosphate backbone of heterologous lipoteichoic acid. J Infect Dis 205(7):1076–1085. https://doi.org/10.1093/infdis/jis022
Song H-S, Choi T-R, Han Y-H, Park Y-L, Park JY, Yang S-Y, Bhatia SK, Gurav R, Kim Y-G, Kim J-S (2020) Increased resistance of a methicillin-resistant Staphylococcus aureus Δ agr mutant with modified control in fatty acid metabolism. AMB Express 10(1):1–10. https://doi.org/10.1186/s13568-020-01000-y
Schneewind O, Missiakas D (2014) Lipoteichoic acids, phosphate-containing polymers in the envelope of gram-positive bacteria. J Bacteriol 196(6):1133–1142. https://doi.org/10.1128/JB.01155-13
Kilelee E, Pokorny A, Yeaman MR, Bayer AS (2010) Lysyl-phosphatidylglycerol attenuates membrane perturbation rather than surface association of the cationic antimicrobial peptide 6W-RP-1 in a model membrane system: implications for daptomycin resistance. Antimicrob Agents Chemother 54(10):4476–4479. https://doi.org/10.1128/AAC.00191-10
Malanovic N, Lohner K (2016) Gram-positive bacterial cell envelopes: The impact on the activity of antimicrobial peptides. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858(5):936–946. https://doi.org/10.1016/j.bbamem.2015.11.004
Oku Y, Kurokawa K, Ichihashi N, Sekimizu K (2004) Characterization of the Staphylococcus aureus mprF gene, involved in lysinylation of phosphatidylglycerol. Microbiology 150(1):45–51. https://doi.org/10.1099/mic.0.26706-0
White DC, Frerman FE (1967) Extraction, characterization, and cellular localization of the lipids of Staphylococcus aureus. J Bacteriol 94(6):1854–1867. https://doi.org/10.1128/jb.94.6.1854-1867.1967
Vinogradov E, Frirdich E, MacLean LL, Perry MB, Petersen BO, Duus JØ, Whitfield C (2002) Structures of lipopolysaccharides from Klebsiella pneumoniae: Elucidation of the structure of the linkage region between core and polysaccharide O chain and identification of the residues at the non-reducing termini of the Ochains. J Biol Chem 277(28):25070–25081. https://doi.org/10.1074/jbc.m202683200
Hobby CR, Herndon JL, Morrow CA, Peters RE, Symes SJ, Giles DK (2019) Exogenous fatty acids alter phospholipid composition, membrane permeability, capacity for biofilm formation, and antimicrobial peptide susceptibility in Klebsiella pneumoniae. Microbiologyopen 8(2):e00635. https://doi.org/10.1002/mbo3.635
Unno, Y.; Sato, Y.; Nishida, S.; Nakano, A.; Nakano, R.; Ubagai, T.; Ono, Y., Acinetobacter baumannii Lipopolysaccharide Influences Adipokine Expression in 3T3-L1 Adipocytes. Mediators of inflammation 2017, 2017. https://doi.org/10.1155/2017/9039302
Jiang X, Yang K, Yuan B, Han M, Zhu Y, Roberts KD, Patil NA, Li J, Gong B, Hancock RE (2020) Molecular dynamics simulations informed by membrane lipidomics reveal the structure–interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii. J Antimicrob Chemother 75(12):3534–3543. https://doi.org/10.1093/jac/dkaa376
Lopalco P, Stahl J, Annese C, Averhoff B, Corcelli A (2017) Identification of unique cardiolipin and monolysocardiolipin species in Acinetobacter baumannii. Sci Rep 7(1):1–12. https://doi.org/10.1038/s41598-017-03214-w
Chao J, Wolfaardt GM, Arts MT (2010) Characterization of Pseudomonas aeruginosa fatty acid profiles in biofilms and batch planktonic cultures. Can J Microbiol 56(12):1028–1039. https://doi.org/10.1139/w10-093
Lam JS, Taylor VL, Islam ST, Hao Y, Kocíncová D (2011) Genetic and functional diversity of Pseudomonas aeruginosa lipopolysaccharide. Front Microbiol 2:118. https://doi.org/10.3389/fmicb.2011.00118
Klein S, Lorenzo C, Hoffmann S, Walther JM, Storbeck S, Piekarski T, Tindall BJ, Wray V, Nimtz M, Moser J (2009) Adaptation of Pseudomonas aeruginosa to various conditions includes tRNA-dependent formation of alanyl-phosphatidylglycerol. Mol Microbiol 71(3):551–565. https://doi.org/10.1111/j.1365-2958.2008.06562.x
Lewenza S, Falsafi R, Bains M, Rohs P, Stupak J, Sprott GD, Hancock RE (2011) The olsA gene mediates the synthesis of an ornithine lipid in Pseudomonas aeruginosa during growth under phosphate-limiting conditions, but is not involved in antimicrobial peptide susceptibility. FEMS Microbiol Lett 320(2):95–102. https://doi.org/10.1111/j.1574-6968.2011.02295.x
Pramanik B, Zechman J, Das P, Bartner P (1990) Bacterial phospholipid analysis by fast atom bombardment mass spectrometry. Biomed Environ Mass Spectrom 19(3):164–170. https://doi.org/10.1002/bms.1200190312
Wilderman PJ, Vasil AI, Martin WE, Murphy RC, Vasil ML (2002) Pseudomonas aeruginosa synthesizes phosphatidylcholine by use of the phosphatidylcholine synthase pathway. J Bacteriol 184(17):4792–4799. https://doi.org/10.1128/jb.184.17.4792-4799.2002
Soberón-Chávez G, Lépine F, Déziel E (2005) Production of rhamnolipids by Pseudomonas aeruginosa. Appl Microbiol Biotechnol 68(6):718–725. https://doi.org/10.1007/s00253-005-0150-3
Bøse B, Gjerde J (1980) Fatty acid patterns in the classification of some representatives of the families Enterobacteriaceae and Vibrionaceae. Microbiology 116(1):41–49. https://doi.org/10.1099/00221287-116-1-41
Gill C, Suisted J (1978) The effects of temperature and growth rate on the proportion of unsaturated fatty acids in bacterial lipids. Microbiology 104(1):31–36. https://doi.org/10.1099/00221287-104-1-31
Kämpfer P, McInroy JA, Glaeser SP (2015) Enterobacter muelleri sp. nov., isolated from the rhizosphere of Zea mays. Int J Syst Evol Microbiol 65(Pt_11):4093–4099. https://doi.org/10.1099/ijsem.0.000547
Davin-Regli A, Lavigne J-P, Pagès J-M (2019) Enterobacter spp.: update on taxonomy, clinical aspects, and emerging antimicrobial resistance. Clin Microbiol Rev 32(4):e00002-19. https://doi.org/10.1128/cmr.00002-19
Epand RM, Epand RF (2009b) Domains in bacterial membranes and the action of antimicrobial agents. Mol BioSyst 5(6):580–587. https://doi.org/10.1016/j.bbamem.2008.08.023
Epand RM, Epand RF, Arnusch CJ, Papahadjopoulos-Sternberg B, Wang G, Shai Y (2010) Lipid clustering by three homologous arginine-rich antimicrobial peptides is insensitive to amino acid arrangement and induced secondary structure. Biochimica et Biophysica Acta (BBA)-Biomembranes 1798(6):1272–1280. https://doi.org/10.1016/j.bbamem.2010.03.012
Villegas, M. V.; Quinn, J. P., Enterobacter species. Antimicrobial therapy and vaccines. Maryland: Apple Trees Productions LLC 2002, 255–63.
Silhavy TJ, Kahne D, Walker S (2010) The bacterial cell envelope. Cold Spring Harbor Perspect Biol 2(5):a000414. https://doi.org/10.1101/cshperspect.a000414
Bogdanov M, Pyrshev K, Yesylevskyy S, Ryabichko S, Boiko V, Ivanchenko P, Kiyamova R, Guan Z, Ramseyer C, Dowhan W (2020) Phospholipid distribution in the cytoplasmic membrane of Gram-negative bacteria is highly asymmetric, dynamic, and cell shape-dependent. Sci Adv 6(23):eaaz6333. https://doi.org/10.1126/sciadv.aaz6333
Paulowski L, Donoghue A, Nehls C, Groth S, Koistinen M, Hagge SO, Böhling A, Winterhalter M, Gutsmann T (2020) The beauty of asymmetric membranes: Reconstitution of the outer membrane of Gram-negative bacteria. Front Cell Dev Biol 8:586. https://doi.org/10.3389/fcell.2020.00586
Cian, M.; Giordano, N.; Mettlach, J.; Minor, K.; Dalebroux, Z., Separation of the Cell Envelope for Gram-negative Bacteria into Inner and Outer Membrane Fractions with Technical Adjustments for Acinetobacter baumannii. Journal of Visualized Experiments: Jove 2020, (158). https://doi.org/10.3791/60517
Raetz CR, Whitfield C (2002) Lipopolysaccharide endotoxins. Annu Rev Biochem 71(1):635–700. https://doi.org/10.1146/annurev.biochem.71.110601.135414
Wang, X.; Quinn, P. J., Endotoxins: lipopolysaccharides of gram-negative bacteria. In Endotoxins: structure, function and recognition, Springer: 2010; pp 3–25. https://doi.org/10.1007/978-90-481-9078-2_1
Li Y, Powell DA, Shaffer SA, Rasko DA, Pelletier MR, Leszyk JD, Scott AJ, Masoudi A, Goodlett DR, Wang X (2012) LPS remodeling is an evolved survival strategy for bacteria. Proc Natl Acad Sci 109(22):8716–8721. https://doi.org/10.1073/pnas.1202908109
Needham BD, Trent MS (2013) Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol 11(7):467–481. https://doi.org/10.1038/nrmicro3047
Trent MS, Stead CM, Tran AX, Hankins JV (2006) Diversity of Endotoxin and Its Impact on Pathogenesis. J Endotoxin Res 12(4):205–223. https://doi.org/10.1179/096805106x118825
Simpson BW, Trent MS (2019) Pushing the envelope: LPS modifications and their consequences. Nat Rev Microbiol 17(7):403–416. https://doi.org/10.1038/s41579-019-0201-x
Maldonado RF, Sá-Correia I, Valvano MA (2016) Lipopolysaccharide modification in Gram-negative bacteria during chronic infection. FEMS Microbiol Rev 40(4):480–493. https://doi.org/10.1093/femsre/fuw007
Moffatt, J. H.; Harper, M.; Harrison, P.; Hale, J. D.; Vinogradov, E.; Seemann, T.; Henry, R.; Crane, B.; St. Michael, F.; Cox, A. D., Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother 2010, 54 (12), 4971-4977. https://doi.org/10.1128/aac.00834-10
Pelletier MR, Casella LG, Jones JW, Adams MD, Zurawski DV, Hazlett KR, Doi Y, Ernst RK (2013) Unique structural modifications are present in the lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob Agents Chemother 57(10):4831–4840. https://doi.org/10.1128/aac.00865-13
Dortet L, Broda A, Bernabeu S, Glupczynski Y, Bogaerts P, Bonnin R, Naas T, Filloux A, Larrouy-Maumus G (2020) Optimization of the MALDIxin test for the rapid identification of colistin resistance in Klebsiella pneumoniae using MALDI-TOF MS. J Antimicrob Chemother 75(1):110–116. https://doi.org/10.1093/jac/dkz405
Olaitan AO, Morand S, Rolain J-M (2014) Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol 5:643. https://doi.org/10.3389/fmicb.2014.00643
Nikaido H (2003) Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67(4):593–656. https://doi.org/10.1128/mmbr.67.4.593-656.2003
Pajerski W, Ochonska D, Brzychczy-Wloch M, Indyka P, Jarosz M, Golda-Cepa M, Sojka Z, Kotarba A (2019) Attachment efficiency of gold nanoparticles by Gram-positive and Gram-negative bacterial strains governed by surface charges. J Nanopart Res 21(8):1–12. https://doi.org/10.1007/s11051-019-4617-z
Percy MG, Gründling A (2014) Lipoteichoic acid synthesis and function in gram-positive bacteria. Annu Rev Microbiol 68:81–100. https://doi.org/10.1146/annurev-micro-091213-112949
Shiraishi T, Yokota S-I, Morita N, Fukiya S, Tomita S, Tanaka N, Okada S, Yokota A (2013) Characterization of a Lactobacillus gasseri JCM 1131T lipoteichoic acid with a novel glycolipid anchor structure. Appl Environ Microbiol 79(10):3315–3318. https://doi.org/10.1128/AEM.00243-13
Gutmann L, Al-Obeid S, Billot-Klein D, Ebnet E, Fischer W (1996) Penicillin tolerance and modification of lipoteichoic acid associated with expression of vancomycin resistance in VanB-type Enterococcus faecium D366. Antimicrob Agents Chemother 40(1):257–259. https://doi.org/10.1128/AAC.40.1.257
Saar-Dover, R.; Bitler, A.; Nezer, R.; Shmuel-Galia, L.; Firon, A.; Shimoni, E.; Trieu-Cuot, P.; Shai, Y., D-alanylation of lipoteichoic acids confers resistance to cationic peptides in group B streptococcus by increasing the cell wall density. 2012. https://doi.org/10.1371/journal.ppat.1002891
Abachin E, Poyart C, Pellegrini E, Milohanic E, Fiedler F, Berche P, Trieu-Cuot P (2002) Formation of d-alanyl-lipoteichoic acid is required for adhesion and virulence of Listeria monocytogenes. Mol Microbiol 43(1):1–14. https://doi.org/10.1046/j.1365-2958.2002.02723.x
Peschel A, Otto M, Jack RW, Kalbacher H, Jung G, Götz F (1999) Inactivation of the dlt Operon inStaphylococcus aureus Confers Sensitivity to Defensins, Protegrins, and Other Antimicrobial Peptides. J Biol Chem 274(13):8405–8410. https://doi.org/10.1074/jbc.274.13.8405
Reichmann NT, Cassona CP, Gründling A (2013) Revised mechanism of D-alanine incorporation into cell wall polymers in Gram-positive bacteria. Microbiology 159(Pt 9):1868. https://doi.org/10.1099/mic.0.069898-0
Rosado H, Turner RD, Foster SJ, Taylor PW (2015) Impact of the β-lactam resistance modifier (−)-epicatechin gallate on the non-random distribution of phospholipids across the cytoplasmic membrane of Staphylococcus aureus. Int J Mol Sci 16(8):16710–16727. https://doi.org/10.3390/ijms160816710
Jones T, Yeaman MR, Sakoulas G, Yang S-J, Proctor RA, Sahl H-G, Schrenzel J, Xiong YQ, Bayer AS (2008) Failures in clinical treatment of Staphylococcus aureus infection with daptomycin are associated with alterations in surface charge, membrane phospholipid asymmetry, and drug binding. Antimicrob Agents Chemother 52(1):269–278. https://doi.org/10.1128/aac.00719-07
Scott JR, Barnett TC (2006) Surface proteins of gram-positive bacteria and how they get there. Annu Rev Microbiol 60:397–423. https://doi.org/10.1146/annurev.micro.60.080805.142256
Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, Samiei M, Kouhi M, Nejati-Koshki K (2013) Liposome: classification, preparation, and applications. Nanoscale Res Lett 8(1):1–9. https://doi.org/10.1186/1556-276X-8-102
Šturm L, Poklar Ulrih N (2021) Basic Methods for Preparation of Liposomes and Studying Their Interactions with Different Compounds, with the Emphasis on Polyphenols. Int J Mol Sci 22(12):6547. https://doi.org/10.3390/ijms22126547
Navas BP, Lohner K, Deutsch G, Sevcsik E, Riske K, Dimova R, Garidel P, Pabst G (2005) Composition dependence of vesicle morphology and mixing properties in a bacterial model membrane system. Biochimica et Biophysica Acta (BBA)-Biomembranes 1716(1):40–48. https://doi.org/10.1016/j.bbamem.2005.08.003
Giuliano CB, Cvjetan N, Ayache J, Walde PJ (2021) Multivesicular Vesicles: Preparation and Applications. ChemSystemsChem 3(2):e2000049. https://doi.org/10.1002/syst.202000049
Mu H, Wang Y, Chu Y, Jiang Y, Hua H, Chu L, Wang K, Wang A, Liu W, Li Y (2018) Multivesicular liposomes for sustained release of bevacizumab in treating laser-induced choroidal neovascularization. Drug Delivery 25(1):1372–1383. https://doi.org/10.1080/10717544.2018.1474967
Gabizon A, Goren D, Cohen R, Barenholz Y (1998) Development of liposomal anthracyclines: from basics to clinical applications. J Control Release 53(1–3):275–279. https://doi.org/10.1016/s0168-3659(97)00261-7
Sherratt SC, Mason RP (2018) Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by X-ray diffraction. Chem Phys Lipid 212:73–79. https://doi.org/10.1016/j.chemphyslip.2018.01.002
Fan M, Xu S, Xia S, Zhang X (2007) Effect of different preparation methods on physicochemical properties of salidroside liposomes. J Agric Food Chem 55(8):3089–3095. https://doi.org/10.1021/jf062935q
Bozzuto G, Molinari A (2015) Liposomes as nanomedical devices. Int J Nanomed 10:975. https://doi.org/10.2147/ijn.s68861
Riaz MK, Riaz MA, Zhang X, Lin C, Wong KH, Chen X, Zhang G, Lu A, Yang Z (2018) Surface functionalization and targeting strategies of liposomes in solid tumor therapy: A review. Int J Mol Sci 19(1):195. https://doi.org/10.3390/ijms19010195
Sakai-Kato K, Yoshida K, Izutsu K-I (2019) Effect of surface charge on the size-dependent cellular internalization of liposomes. Chem Phys Lipids 224:104726. https://doi.org/10.1016/j.chemphyslip.2019.01.004
Tuerkova A, Kabelka I, Králová T, Sukeník L, Pokorná Š, Hof M, Vácha R (2020) Effect of helical kink in antimicrobial peptides on membrane pore formation. Elife 9:e47946. https://doi.org/10.7554/eLife.47946
Dombach JL, Quintana JL, Nagy TA, Wan C, Crooks AL, Yu H, Su C-C, Yu EW, Shen J, Detweiler CS (2020) A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids. PLoS pathogens 16(12):e1009119. https://doi.org/10.1371/journal.ppat.1009119
Jamasbi E, Batinovic S, Sharples RA, Sani M-A, Robins-Browne RM, Wade JD, Separovic F, Hossain MA (2014) Melittin peptides exhibit different activity on different cells and model membranes. Amino Acids 46(12):2759–2766. https://doi.org/10.1007/s00726-014-1833-9
Kumagai A, Dupuy FG, Arsov Z, Elhady Y, Moody D, Ernst RK, Deslouches B, Montelaro RC, Di YP, Tristram-Nagle S (2019) Elastic behavior of model membranes with antimicrobial peptides depends on lipid specificity and d-enantiomers. Soft Matter 15(8):1860–1868. https://doi.org/10.1039/c8sm02180e
Pérez-Peinado C, Dias SA, Domingues MM, Benfield AH, Freire JM, Rádis-Baptista G, Gaspar D, Castanho MA, Craik DJ, Henriques ST (2018) Mechanisms of bacterial membrane permeabilization by crotalicidin (Ctn) and its fragment Ctn (15–34), antimicrobial peptides from rattlesnake venom. J Biol Chem 293(5):1536–1549. https://doi.org/10.1074/jbc.RA117.000125
Malishev R, Abbasi R, Jelinek R, Chai L (2018) Bacterial model membranes reshape fibrillation of a functional amyloid protein. Biochemistry 57(35):5230–5238. https://doi.org/10.1021/acs.biochem.8b00002
Kahveci Z, Vázquez-Guilló R, Mira A, Martinez L, Falcó A, Mallavia R, Mateo CR (2016) Selective recognition and imaging of bacterial model membranes over mammalian ones by using cationic conjugated polyelectrolytes. Analyst 141(22):6287–6296. https://doi.org/10.1039/c6an01427e
Lopes SC, Neves CS, Eaton P, Gameiro P (2012) Improved model systems for bacterial membranes from differing species: the importance of varying composition in PE/PG/cardiolipin ternary mixtures. Mol Membr Biol 29(6):207–217. 152. https://doi.org/10.3109/09687688.2012.700491
Cheng JT, Hale JD, Elliott M, Hancock RE, Straus SK (2011) The importance of bacterial membrane composition in the structure and function of aurein 2.2 and selected variants. Biochimica Et Biophysica Acta (BBA)-Biomembranes 1808(3):622–633. https://doi.org/10.1016/j.bbamem.2010.11.025
Marín-Menéndez A, Montis C, Díaz-Calvo T, Carta D, Hatzixanthis K, Morris CJ, McArthur M, Berti D (2017) Antimicrobial nanoplexes meet model bacterial membranes: the key role of Cardiolipin. Sci Rep 7(1):1–13. https://doi.org/10.1038/srep41242
Fernandez DI, Sani M-A, Gehman JD, Hahm K-S, Separovic F (2011) Interactions of a synthetic Leu–Lys-rich antimicrobial peptide with phospholipid bilayers. Eur Biophys J 40(4):471–480. https://doi.org/10.1007/s00249-010-0660-5
Domenech O, Francius G, Tulkens PM, Van Bambeke F, Dufrêne Y, Mingeot-Leclercq M-P (2009) Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: effect on membrane permeability and nanoscale lipid membrane organization. Biochimica et Biophysica Acta (BBA)-Biomembranes 1788(9):1832–1840. https://doi.org/10.1016/j.bbamem.2009.05.003
Pinheiro M, Nunes CU, Caio JM, Moiteiro C, Lúcio M, Brezesinski G, Reis S (2013) The influence of rifabutin on human and bacterial membrane models: Implications for its mechanism of action. J Phys Chem B 117(20):6187–6193. https://doi.org/10.1021/jp403073v
D’Errico G, Silipo A, Mangiapia G, Vitiello G, Radulescu A, Molinaro A, Lanzetta R, Paduano L (2010) Characterization of liposomes formed by lipopolysaccharides from Burkholderia cenocepacia, Burkholderia multivorans and Agrobacterium tumefaciens: from the molecular structure to the aggregate architecture. Phys Chem Chem Phys 12(41):13574–13585. https://doi.org/10.1039/C0CP00066C
Furusato T, Horie F, Matsubayashi HT, Amikura K, Kuruma Y, Ueda T (2018) De novo synthesis of basal bacterial cell division proteins FtsZ, FtsA, and ZipA inside giant vesicles. ACS Synth Biol 7(4):953–961. https://doi.org/10.1021/acssynbio.7b00350
Kiss B, Bozó T, Mudra D, Tordai H, Herényi L, Kellermayer M (2021) Development, structure and mechanics of a synthetic E. coli outer membrane model. Nanoscale Adv 3(3):755–766. https://doi.org/10.1039/D0NA00977F
Jiménez M, Martos A, Vicente M, Rivas G (2011) Reconstitution and organization of Escherichia coli proto-ring elements (FtsZ and FtsA) inside giant unilamellar vesicles obtained from bacterial inner membranes. J Biol Chem 286(13):11236–11241. https://doi.org/10.1074/jbc.m110.194365
Sikder A, Sarkar J, Barman R, Ghosh S (2019) Directional Supramolecular Assembly of π-Amphiphiles with Tunable Surface Functionality and Impact on the Antimicrobial Activity. J Phys Chem B 123(33):7169–7177. https://doi.org/10.1021/acs.jpcb.9b05193
Kubiak J, Brewer J, Hansen S, Bagatolli LA (2011) Lipid lateral organization on giant unilamellar vesicles containing lipopolysaccharides. Biophys J 100(4):978–986. https://doi.org/10.1016/j.bpj.2011.01.012
Mohanan G, Nair KS, Nampoothiri KM, Bajaj H (2020) Engineering bio-mimicking functional vesicles with multiple compartments for quantifying molecular transport. Chem Sci 11(18):4669–4679. https://doi.org/10.1039/D0SC00084A
Ruhr E, Sahl H-G (1985) Mode of action of the peptide antibiotic nisin and influence on the membrane potential of whole cells and on cytoplasmic and artificial membrane vesicles. Antimicrob Agents Chemother 27(5):841–845. https://doi.org/10.1128/aac.27.5.841
Bharatiya B, Wang G, Rogers SE, Pedersen JS, Mann S, Briscoe WH (2021) Mixed liposomes containing gram-positive bacteria lipids: Lipoteichoic acid (LTA) induced structural changes. Colloids Surf B 199:111551. https://doi.org/10.1016/j.colsurfb.2020.111551
Saliba A-E, Vonkova I, Ceschia S, Findlay GM, Maeda K, Tischer C, Deghou S, Van Noort V, Bork P, Pawson T (2014) A quantitative liposome microarray to systematically characterize protein-lipid interactions. Nat Methods 11(1):47–50. https://doi.org/10.1038/nmeth.2734
Turner M, Singhrao SK, Dennison SR, Morton LHG, Crean S (2015) Challenging the Clostridium botulinum toxin type A (BoNT/A) with a selection of microorganisms by culture methods and extended storage of used vials to assess the loss of sterility. J Dent Appl 2(5):223–228
Som A, Tew GN (2008) Influence of lipid composition on membrane activity of antimicrobial phenylene ethynylene oligomers. J Phys Chem B 112(11):3495–3502. https://doi.org/10.1021/jp077487j
Samuel R, Gillmor S (2016) Membrane phase characteristics control NA-CATH activity. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858(9):1974–1982. https://doi.org/10.1016/j.bbamem.2016.05.015
Sborgi L, Rühl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Müller DJ, Broz P, Hiller S (2016) GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35(16):1766–1778. https://doi.org/10.15252/embj.201694696
Carrasco-López C, Rojas-Altuve A, Zhang W, Hesek D, Lee M, Barbe S, André I, Ferrer P, Silva-Martin N, Castro GR (2011) Crystal structures of bacterial peptidoglycan amidase AmpD and an unprecedented activation mechanism. J Biol Chem 286(36):31714–31722. https://doi.org/10.1074/jbc.M111.264366
Sasaki M, Nishikawa H, Suzuki S, Moser M, Huber M, Sawasato K, Matsubayashi HT, Kumazaki K, Tsukazaki T, Kuruma Y (2019) The bacterial protein YidC accelerates MPIase-dependent integration of membrane proteins. J Biol Chem 294(49):18898–18908. https://doi.org/10.1074/jbc.ra119.011248
Cheng M, Huang JX, Ramu S, Butler MS, Cooper MA (2014) Ramoplanin at bactericidal concentrations induces bacterial membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother 58(11):6819–6827. https://doi.org/10.1128/AAC.00061-14
Lombardi L, Stellato MI, Oliva R, Falanga A, Galdiero M, Petraccone L, D’Errico G, De Santis A, Galdiero S, Del Vecchio P (2017) Antimicrobial peptides at work: interaction of myxinidin and its mutant WMR with lipid bilayers mimicking the P. aeruginosa and E. coli membranes. Sci Rep 7(1):1–15. https://doi.org/10.1038/srep44425
Zhang T, Muraih JK, Tishbi N, Herskowitz J, Victor RL, Silverman J, Uwumarenogie S, Taylor SD, Palmer M, Mintzer E (2014) Cardiolipin prevents membrane translocation and permeabilization by daptomycin. J Biol Chem 289(17):11584–11591. https://doi.org/10.1074/jbc.m114.554444
Brian Chia C, Gong Y, Bowie JH, Zuegg J, Cooper MA (2011) Membrane binding and perturbation studies of the antimicrobial peptides caerin, citropin, and maculatin. Pept Sci 96(2):147–157. https://doi.org/10.1002/bip.21438
Su Y, Waring AJ, Ruchala P, Hong M (2011) Structures of β-hairpin antimicrobial protegrin peptides in lipopolysaccharide membranes: mechanism of gram selectivity obtained from solid-state nuclear magnetic resonance. Biochemistry 50(12):2072–2083. https://doi.org/10.1021/bi101975v
Hancock R, Nikaido H (1978) Outer membranes of gram-negative bacteria. XIX. Isolation from Pseudomonas aeruginosa PAO1 and use in reconstitution and definition of the permeability barrier. J Bacteriol 136(1):381–390. https://doi.org/10.1128/jb.136.1.381-390.1978
Ciesielski F, Griffin DC, Rittig M, Moriyón I, Bonev BB (2013) Interactions of lipopolysaccharide with lipid membranes, raft models—A solid state NMR study. Biochimica et Biophysica Acta (BBA)-Biomembranes 1828(8):1731–1742. https://doi.org/10.1016/j.bbamem.2013.03.029
Lee E-H, Collatz E, Trias J, Gutmann L (1992) Diffusion of β-lactam antibiotics into proteoliposomes reconstituted with outer membranes of isogenic imipenem-susceptible and-resistant strains of Enterobacter cloacae. Microbiology 138(11):2347–2351. https://doi.org/10.1099/00221287-138-11-2347
Mitchell NJ, Seaton P, Pokorny A (2016) Branched phospholipids render lipid vesicles more susceptible to membrane-active peptides. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858(5):988–994. https://doi.org/10.1016/j.bbamem.2015.10.014
Rideau E, Dimova R, Schwille P, Wurm FR, Landfester K (2018) Liposomes and polymersomes: a comparative review towards cell mimicking. Chem Soc Rev 47(23):8572–8610. https://doi.org/10.1039/C8CS00162F
Weinberger A, Tsai F-C, Koenderink GH, Schmidt TF, Itri R, Meier W, Schmatko T, Schröder A, Marques C (2013) Gel-assisted formation of giant unilamellar vesicles. Biophys J 105(1):154–164. https://doi.org/10.1016/j.bpj.2013.05.024
Göpfrich K, Haller B, Staufer O, Dreher Y, Mersdorf U, Platzman I, Spatz JP (2019) One-pot assembly of complex giant unilamellar vesicle-based synthetic cells. ACS Synth Biol 8(5):937–947. https://doi.org/10.1021/acssynbio.9b00034
Pautot S, Frisken BJ, Weitz D (2003) Engineering asymmetric vesicles. Proc Natl Acad Sci 100(19):10718–10721. https://doi.org/10.1073/pnas.1931005100
Nkanga, C. I.; Bapolisi, A. M.; Okafor, N. I.; Krause, R. W. M., General perception of liposomes: formation, manufacturing and applications. Liposomes-advances and perspectives 2019. https://doi.org/10.5772/intechopen.84255
Eeman M, Deleu M (2010) From biological membranes to biomimetic model membranes. Biotechnol Agron Soc Environ 14(4):719–736.
Vestergaard MD, Hamada T, Takagi M (2008) Using model membranes for the study of amyloid beta: lipid interactions and neurotoxicity. Biotechnol Bioeng 99(4):753–763. https://doi.org/10.1002/bit.21731
Schmid EM, Richmond DL, Fletcher DA (2015) Reconstitution of proteins on electroformed giant unilamellar vesicles. Methods Cell Biol 128:319–338. https://doi.org/10.1016/bs.mcb.2015.02.004
Belegrinou S, Menon S, Dobrunz D, Meier W (2011) Solid-supported polymeric membranes. Soft Matter 7(6):2202–2210. https://doi.org/10.1039/C0SM01163K
Sackmann E (1996) Supported membranes: scientific and practical applications. Science 271(5245):43–48. https://doi.org/10.1126/science.271.5245.43
Foglia F, Lawrence M, Barlow D (2015) Studies of model biological and bio-mimetic membrane structure: reflectivity vs diffraction, a critical comparison. Curr Opin Colloid Interface Sci 20(4):235–243. https://doi.org/10.1016/j.cocis.2015.08.001
Li C, Wang M, Ferguson M, Zhan W (2015) Phospholipid/aromatic thiol hybrid bilayers. Langmuir 31(18):5228–5234. https://doi.org/10.1021/acs.langmuir.5b00476
Köper I (2007) Insulating tethered bilayer lipid membranes to study membrane proteins. Mol BioSyst 3(10):651–657. https://doi.org/10.1039/B707168J
Girard-Egrot AP, Maniti O (2021) Why Do Tethered-Bilayer Lipid Membranes Suit for Functional Membrane Protein Reincorporation? Appl Sci 11(11):4876. https://doi.org/10.3390/app11114876
Kurniawan J, de Ventrici Souza JOF, Dang AT, Liu GY, Kuhl TL (2018) Preparation and characterization of solid-supported lipid bilayers formed by Langmuir-Blodgett deposition: a tutorial. Langmuir 34(51):15622–15639. https://doi.org/10.1021/acs.langmuir.8b03504
Richter RP, Him JLK, Brisson A (2003) Supported lipid membranes. Mater Today 6(11):32–37. https://doi.org/10.1016/S1369-7021(03)01129-5
Clifton LA, Campbell RA, Sebastiani F, Campos-Terán J, Gonzalez-Martinez JF, Björklund S, Sotres J, Cárdenas M (2020) Design and use of model membranes to study biomolecular interactions using complementary surface-sensitive techniques. Adv Colloid Interface Sci 277:102118. https://doi.org/10.1016/j.cis.2020.102118
Giess F, Friedrich MG, Heberle J, Naumann RL, Knoll W (2004) The protein-tethered lipid bilayer: A novel mimic of the biological membrane. Biophys J 87(5):3213–3220. https://doi.org/10.1529/biophysj.104.046169
Ferhan AR, Jackman JA, Cho N-J (2017) Probing Spatial Proximity of Supported Lipid Bilayers to Silica Surfaces by Localized Surface Plasmon Resonance Sensing. Anal Chem 89(7):4301–4308. https://doi.org/10.1021/acs.analchem.7b00370
Wittenberg NJ, Wootla B, Jordan LR, Denic A, Warrington AE, Oh S-H, Rodriguez M (2014) Applications of SPR for the characterization of molecules important in the pathogenesis and treatment of neurodegenerative diseases. Expert Rev Neurother 14(4):449–463. https://doi.org/10.1586/14737175.2014.896199
Steltenkamp S, Müller MM, Deserno M, Hennesthal C, Steinem C, Janshoff A (2006) Mechanical Properties of Pore-Spanning Lipid Bilayers Probed by Atomic Force Microscopy. Biophys J 91(1):217–226. https://doi.org/10.1529/biophysj.106.081398
Weiss SA, Bushby RJ, Evans SD, Jeuken LJ (2010) A study of cytochrome bo3 in a tethered bilayer lipid membrane. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1797(12):1917–1923. https://doi.org/10.1016/j.bbabio.2010.01.012
Clifton LA, Skoda MW, Daulton EL, Hughes AV, Le Brun AP, Lakey JH, Holt SA (2013) Asymmetric phospholipid: lipopolysaccharide bilayers; a Gram-negative bacterial outer membrane mimic. J R Soc Interface 10(89):20130810. https://doi.org/10.1098/rsif.2013.0810
Paracini N, Clifton LA, Skoda MW, Lakey JH (2018) Liquid crystalline bacterial outer membranes are critical for antibiotic susceptibility. Proc Natl Acad Sci 115(32):E7587–E7594. https://doi.org/10.1073/pnas.1803975115
Hughes AV, Patel DS, Widmalm G, Klauda JB, Clifton LA, Im W (2019) Physical properties of bacterial outer membrane models: neutron reflectometry & molecular simulation. Biophys J 116(6):1095–1104. https://doi.org/10.1016/j.bpj.2019.02.001
Dodd CE, Johnson BR, Jeuken LJ, Bugg TD, Bushby RJ, Evans SD, Native E (2008) coli inner membrane incorporation in solid-supported lipid bilayer membranes. Biointerphases 3(2):FA59–FA67. https://doi.org/10.1116/1.2896113
Michel J, Wang Y, Kiesel I, Gerelli Y, Rosilio V (2017) Disruption of asymmetric lipid bilayer models mimicking the outer membrane of gram-negative bacteria by an active plasticin. Langmuir 33(41):11028–11039. https://doi.org/10.1021/acs.langmuir.7b02864
Adhyapak P, Srivatsav AT, Mishra M, Singh A, Narayan R, Kapoor S (2020) Dynamical organization of compositionally distinct inner and outer membrane lipids of mycobacteria. Biophys J 118(6):1279–1291. https://doi.org/10.1016/j.bpj.2020.01.027
Nakatani Y, Shimaki Y, Dutta D, Muench SP, Ireton K, Cook GM, Jeuken LJ (2019) Unprecedented properties of phenothiazines unraveled by a NDH-2 bioelectrochemical assay platform. J Am Chem Soc 142(3):1311–1320. https://doi.org/10.1021/jacs.9b10254
Hoiles W, Krishnamurthy V (2015) Dynamic modeling of antimicrobial pore formation in engineered tethered membranes. IEEE Trans Mol Biol Multi-Scale Commun 1(3):265–276. https://doi.org/10.1109/TMBMC.2016.2537299
Schneck E, Oliveira RG, Rehfeldt F, Demé B, Brandenburg K, Seydel U, Tanaka M (2009) Mechanical properties of interacting lipopolysaccharide membranes from bacteria mutants studied by specular and off-specular neutron scattering. Phys Rev E 80(4):041929. https://doi.org/10.1103/PhysRevE.80.041929
Lee, T.-H.; Hofferek, V.; Sani, M.-a.; Separovic, F.; Reid, G.; Aguilar, M. I., The Impact of Antibacterial Peptides on Bacterial Lipid Membranes Depends on Stage of Growth. Faraday Discussions 2020. https://doi.org/10.1039/D0FD00052C
Nedelkovski V, Schwaighofer A, Wraight CA, Nowak C, Naumann RL (2013) Surface-enhanced infrared absorption spectroscopy (SEIRAS) of light-activated photosynthetic reaction centers from Rhodobacter sphaeroides reconstituted in a biomimetic membrane system. J Phys Chem C 117(32):16357–16363. https://doi.org/10.1021/jp4056347
Niu L, Wohland T, Knoll W, Köper I (2017) Interaction of a synthetic antimicrobial peptide with a model bilayer platform mimicking bacterial membranes. Biointerphases 12(4):04E404. https://doi.org/10.1116/1.5001020
Sharma P, Parthasarathi S, Patil N, Waskar M, Raut JS, Puranik M, Ayappa KG, Basu JK (2020) Assessing barriers for antimicrobial penetration in complex asymmetric bacterial membranes: A case study with thymol. Langmuir 36(30):8800–8814. https://doi.org/10.1021/acs.langmuir.0c01124
McGillivray DJ, Valincius G, Heinrich F, Robertson JW, Vanderah DJ, Febo-Ayala W, Ignatjev I, Lösche M, Kasianowicz JJ (2009) Structure of functional Staphylococcus aureus α-hemolysin channels in tethered bilayer lipid membranes. Biophys J 96(4):1547–1553. https://doi.org/10.1016/j.bpj.2008.11.020
Dupuy FG, Pagano I, Andenoro K, Peralta MF, Elhady Y, Heinrich F, Tristram-Nagle S (2018) Selective interaction of colistin with lipid model membranes. Biophys J 114(4):919–928. https://doi.org/10.1016/j.bpj.2017.12.027
Li X, Smith AW (2019) Quantifying Lipid Mobility and Peptide Binding for Gram-Negative and Gram-Positive Model Supported Lipid Bilayers. J Phys Chem B 123(49):10433–10440. https://doi.org/10.1021/acs.jpcb.9b09709
Clifton LA, Holt SA, Hughes AV, Daulton EL, Arunmanee W, Heinrich F, Khalid S, Jefferies D, Charlton TR, Webster JR (2015) An accurate in vitro model of the E. coli envelope. Angew Chem Int Ed 54(41):11952–11955. https://doi.org/10.1002/anie.201504287
Hsia C-Y, Chen L, Singh RR, DeLisa MP, Daniel S (2016) A molecularly complete planar bacterial outer membrane platform. Sci Rep 6(1):1–14. https://doi.org/10.1038/srep32715
Thomas CJ, Surolia N, Surolia A (1999) Surface plasmon resonance studies resolve the enigmatic endotoxin neutralizing activity of polymyxin B. J Biol Chem 274(42):29624–29627. https://doi.org/10.1074/jbc.274.42.29624
Spencelayh MJ, Cheng Y, Bushby RJ, Bugg TD, Li JJ, Henderson PJ, O’Reilly J, Evans SD (2006) Antibiotic action and peptidoglycan formation on tethered lipid bilayer membranes. Angewandte Chemie 118(13):2165–2170. https://doi.org/10.1002/ange.200504035
Mirandela GD, Tamburrino G, Hoskisson PA, Zachariae U, Javelle A (2019) The lipid environment determines the activity of the Escherichia coli ammonium transporter AmtB. FASEB J 33(2):1989–1999. https://doi.org/10.1096/fj.201800782r
Maccarini M, Gayet L, Alcaraz J-P, Liguori L, Stidder B, Watkins EB, Lenormand J-L, Martin DK (2017) Functional characterization of cell-free expressed OprF porin from Pseudomonas aeruginosa stably incorporated in tethered lipid bilayers. Langmuir 33(38):9988–9996. https://doi.org/10.1021/acs.langmuir.7b01731
Jeuken LJ, Connell SD, Henderson PJ, Gennis RB, Evans SD, Bushby RJ (2006) Redox enzymes in tethered membranes. J Am Chem Soc 128(5):1711–1716. https://doi.org/10.1021/ja056972u
Jeuken LJ, Connell SD, Nurnabi M, O’Reilly J, Henderson PJ, Evans SD, Bushby RJ (2005) Direct electrochemical interaction between a modified gold electrode and a bacterial membrane extract. Langmuir 21(4):1481–1488. https://doi.org/10.1021/la047732f
Mohamed Z, Shin J-H, Ghosh S, Sharma AK, Pinnock F, Bint E Naser Farnush S, Dörr T, Daniel S (2021) Clinically relevant bacterial outer membrane models for antibiotic screening applications. ACS Infect Dis 7(9):2707–2722. https://doi.org/10.1021/acsinfecdis.1c00217
Zang M, MacDermott-Opeskin H, Adams FG, Naidu V, Waters JK, Carey AB, Ashenden A, McLean KT, Brazel EB, Jiang J-H, Panizza A, Trappetti C, Paton JC, Peleg AY, Köper I, Paulsen IT, Hassan KA, O’Mara ML, Eijkelkamp BA (2021) The Membrane Composition Defines the Spatial Organization and Function of a Major Acinetobacter baumannii Drug Efflux System. mBio 12(3):1–6. https://doi.org/10.1128/mBio.01070-21
Alghalayini A, Garcia A, Berry T, Cranfield CG (2019) The use of tethered bilayer lipid membranes to identify the mechanisms of antimicrobial peptide interactions with lipid bilayers. Antibiotics 8(1):12. https://doi.org/10.3390/antibiotics8010012
Tamm LK, McConnell HM (1985) Supported phospholipid bilayers. Biophys J 47(1):105–113. https://doi.org/10.1016/s0006-3495(85)83882-0
Tanaka M, Sackmann E (2005) Polymer-supported membranes as models of the cell surface. Nature 437(7059):656–663. https://doi.org/10.1038/nature04164
Naumann C, Knoll W, Frank C (2001) Hindered Diffusion in Polymer-Tethered Membranes: A Monolayer Study at the Air− Water Interface. Biomacromol 2(4):1097–1103. https://doi.org/10.1021/bm010022t
Naumann CA, Prucker O, Lehmann T, Rühe J, Knoll W, Frank CW (2002) The polymer-supported phospholipid bilayer: Tethering as a new approach to substrate− membrane stabilization. Biomacromol 3(1):27–35. https://doi.org/10.1021/bm0100211
Deleu M, Crowet J-M, Nasir MN, Lins L (2014) Complementary biophysical tools to investigate lipid specificity in the interaction between bioactive molecules and the plasma membrane: A review. Biochimica et Biophysica Acta (BBA)-Biomembranes 1838(12):3171–3190. https://doi.org/10.1016/j.bbamem.2014.08.023
Lyman E, Hsieh C-L, Eggeling C (2018) From dynamics to membrane organization: experimental breakthroughs occasion a “modeling manifesto.” Biophys J 115(4):595–604. https://doi.org/10.1016/j.bpj.2018.07.012
Nickels JD, Smith JC, Cheng X (2015) Lateral organization, bilayer asymmetry, and inter-leaflet coupling of biological membranes. Chem Phys Lipid 192:87–99. https://doi.org/10.1016/j.chemphyslip.2015.07.012
Maity PC, Yang J, Klaesener K, Reth M (2015) The nanoscale organization of the B lymphocyte membrane. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1853(4):830–840. https://doi.org/10.1016/j.bbamcr.2014.11.010
Marrink SJ, Corradi V, Souza PC, Ingólfsson HI, Tieleman DP, Sansom MS (2019) Computational modeling of realistic cell membranes. Chem Rev 119(9):6184–6226. https://doi.org/10.1021/acs.chemrev.8b00460
Ingólfsson HI, Arnarez C, Periole X, Marrink SJ (2016) Computational ‘microscopy’of cellular membranes. J Cell Sci 129(2):257–268. https://doi.org/10.1242/jcs.176040
MacKerell AD Jr (2004) Empirical force fields for biological macromolecules: overview and issues. J Comput Chem 25(13):1584–1604. https://doi.org/10.1002/jcc.20082
Mori T, Miyashita N, Im W, Feig M, Sugita Y (2016) Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858(7):1635–1651. https://doi.org/10.1016/j.bbamem.2015.12.032
Matamoros-Recio A, Franco-Gonzalez JF, Forgione RE, Torres-Mozas A, Silipo A, Martín-Santamaría S (2021) Understanding the Antibacterial Resistance: Computational Explorations in Bacterial Membranes. ACS Omega 6(9):6041–6054. https://doi.org/10.1021/acsomega.0c05590
Bennett WD, Tieleman DP (2013) Computer simulations of lipid membrane domains. Biochimica et Biophysica Acta (BBA)-Biomembranes 1828(8):1765–1776. https://doi.org/10.1016/j.bbamem.2013.03.004
Chan C, Wen H, Lu L, Fan J (2015) Multiscale molecular dynamics simulations of membrane remodeling by Bin/Amphiphysin/Rvs family proteins. Chinese Physics B 25(1):018707. https://doi.org/10.1088/1674-1056/25/1/018707
Kabedev A, Hossain S, Hubert M, Larsson P, Bergström CA (2021) Molecular dynamics simulations reveal membrane interactions for poorly water-soluble drugs: impact of bile solubilization and drug aggregation. J Pharm Sci 110(1):176–185. https://doi.org/10.1016/j.xphs.2020.10.061
Khan SH, Prakash A, Pandey P, Lynn AM, Islam A, Hassan MI, Ahmad F (2019) Protein folding: Molecular dynamics simulations and in vitro studies for probing mechanism of urea-and guanidinium chloride-induced unfolding of horse cytochrome-c. Int J Biol Macromol 122:695–704. https://doi.org/10.1016/j.ijbiomac.2018.10.186
Lazim R, Suh D, Choi S (2020) Advances in molecular dynamics simulations and enhanced sampling methods for the study of protein systems. Int J Mol Sci 21(17):6339. https://doi.org/10.3390/ijms21176339
Liu Y, de Vries AH, Pezeshkian W, Marrink SJ (2021) Capturing Membrane Phase Separation by Dual Resolution Molecular Dynamics Simulations. J Chem Theory Comput 17(9):5876–5884. https://doi.org/10.1021/acs.jctc.1c00151
Parkin J, Chavent M, Khalid S (2015) Molecular simulations of Gram-negative bacterial membranes: a vignette of some recent successes. Biophys J 109(3):461–468. https://doi.org/10.1016/j.bpj.2015.06.050
Reddy T, Sansom MS (2016) Computational virology: from the inside out. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858(7):1610–1618. https://doi.org/10.1016/j.bbamem.2016.02.007
Singharoy A, Schulten K (2017) Atom-Resolved View of a Cell Organelle on a Computational Microscope. Biophys J 112(3):176a. https://doi.org/10.1016/j.bpj.2016.11.973
Balusek C, Gumbart JC (2016) Role of the native outer-membrane environment on the transporter BtuB. Biophys J 111(7):1409–1417. https://doi.org/10.1016/j.bpj.2016.08.033
Baltoumas FA, Hamodrakas SJ, Iconomidou VA (2019) The gram-negative outer membrane modeler: Automated building of lipopolysaccharide-rich bacterial outer membranes in four force fields. J Comput Chem 40(18):1727–1734. https://doi.org/10.1002/jcc.25823
Gao Y, Lee J, Widmalm G, Im W (2020) Modeling and Simulation of Bacterial Outer Membranes with Lipopolysaccharides and Enterobacterial Common Antigen. J Phys Chem B 124(28):5948–5956. https://doi.org/10.1021/acs.jpcb.0c03353
Kholina EG, Kovalenko IB, Bozdaganyan ME, Strakhovskaya MG, Orekhov PS (2020) Cationic antiseptics facilitate pore formation in model bacterial membranes. J Phys Chem B 124(39):8593–8600. https://doi.org/10.1021/acs.jpcb.0c07212
Li Y, Guo H (2013) Atomistic simulations of an antimicrobial molecule interacting with a model bacterial membrane. Theoret Chem Acc 132(1):1–8. https://doi.org/10.1007/s00214-012-1303-y
Abellón-Ruiz J, Kaptan SS, Baslé A, Claudi B, Bumann D, Kleinekathöfer U, van den Berg B (2017) Structural basis for maintenance of bacterial outer membrane lipid asymmetry. Nat Microbiol 2(12):1616–1623. https://doi.org/10.1038/s41564-017-0046-x
Berglund NA, Piggot TJ, Jefferies D, Sessions RB, Bond PJ, Khalid S (2015) Interaction of the antimicrobial peptide polymyxin B1 with both membranes of E. coli: a molecular dynamics study. PLoS Comput Biol 11(4):e1004180. https://doi.org/10.1371/journal.pcbi.1004180
Hsu P-C, Samsudin F, Shearer J, Khalid S (2017a) It is complicated: curvature, diffusion, and lipid sorting within the two membranes of Escherichia coli. J Phys Chem Lett 8(22):5513–5518. https://doi.org/10.1021/acs.jpclett.7b02432
Hsu, P. C.; Bruininks, B. M.; Jefferies, D.; Cesar Telles de Souza, P.; Lee, J.; Patel, D. S.; Marrink, S. J.; Qi, Y.; Khalid, S.; Im, W., CHARMM‐GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides. Wiley Online Library: 2017. https://doi.org/10.1002/jcc.24895
Ma H, Khan A, Nangia S (2017a) Dynamics of OmpF trimer formation in the bacterial outer membrane of Escherichia coli. Langmuir 34(19):5623–5634. https://doi.org/10.1021/acs.langmuir.7b02653
Mehmood S, Corradi V, Choudhury HG, Hussain R, Becker P, Axford D, Zirah S, Rebuffat S, Tieleman DP, Robinson CV (2016) Structural and functional basis for lipid synergy on the activity of the antibacterial peptide ABC transporter McjD. J Biol Chem 291(41):21656–21668. https://doi.org/10.1074/jbc.M116.732107
Orekhov PS, Kholina EG, Bozdaganyan ME, Nesterenko AM, Kovalenko IB, Strakhovskaya MG (2018) Molecular mechanism of uptake of cationic photoantimicrobial phthalocyanine across bacterial membranes revealed by molecular dynamics simulations. J Phys Chem B 122(14):3711–3722. https://doi.org/10.1021/acs.jpcb.7b11707
Shearer J, Jefferies D, Khalid S (2019) Outer membrane proteins OmpA, FhuA, OmpF, EstA, BtuB, and OmpX have unique lipopolysaccharide fingerprints. J Chem Theory Comput 15(4):2608–2619. https://doi.org/10.1021/acs.jctc.8b01059
Shearer J, Khalid S (2018) Communication between the leaflets of asymmetric membranes revealed from coarse-grain molecular dynamics simulations. Sci Rep 8(1):1–6. https://doi.org/10.1038/s41598-018-20227-1
Rice A, Wereszczynski J (2018) Atomistic scale effects of lipopolysaccharide modifications on bacterial outer membrane defenses. Biophys J 114(6):1389–1399. https://doi.org/10.1016/j.bpj.2018.02.006
Patel DS, Re S, Wu EL, Qi Y, Klebba PE, Widmalm G, Yeom MS, Sugita Y, Im W (2016) Dynamics and interactions of OmpF and LPS: influence on pore accessibility and ion permeability. Biophys J 110(4):930–938. https://doi.org/10.1016/j.bpj.2016.01.002
Piggot TJ, Holdbrook DA, Khalid S (2011) Electroporation of the E. coli and S. aureus membranes: molecular dynamics simulations of complex bacterial membranes. J Phys Chem B 115(45):13381–13388. https://doi.org/10.1021/jp207013v
Carpenter TS, Parkin J, Khalid S (2016) The free energy of small solute permeation through the Escherichia coli outer membrane has a distinctly asymmetric profile. J Phys Chem Lett 7(17):3446–3451. https://doi.org/10.1021/acs.jpclett.6b01399
Fleming PJ, Patel DS, Wu EL, Qi Y, Yeom MS, Sousa MC, Fleming KG, Im W (2016) BamA POTRA domain interacts with a native lipid membrane surface. Biophys J 110(12):2698–2709. https://doi.org/10.1016/j.bpj.2016.05.010
Wu EL, Engström O, Jo S, Stuhlsatz D, Yeom MS, Klauda JB, Widmalm G, Im W (2013) Molecular dynamics and NMR spectroscopy studies of E. coli lipopolysaccharide structure and dynamics. Biophys J 105(6):1444–1455. https://doi.org/10.1016/j.bpj.2013.08.002
Wu EL, Fleming PJ, Yeom MS, Widmalm G, Klauda JB, Fleming KG, Im W (2014) E. coli outer membrane and interactions with OmpLA. Biophys J 106(11):2493–2502. https://doi.org/10.1016/j.bpj.2014.04.024
Duay SS, Sharma G, Prabhakar R, Angeles-Boza AM, May ER (2019) Molecular dynamics investigation into the effect of zinc (II) on the structure and membrane interactions of the antimicrobial peptide Clavanin A. J Phys Chem B 123(15):3163–3176. https://doi.org/10.1021/acs.jpcb.8b11496
Khondker A, Dhaliwal AK, Saem S, Mahmood A, Fradin C, Moran-Mirabal J, Rheinstädter MC (2019) Membrane charge and lipid packing determine polymyxin-induced membrane damage. Commun Biol 2(1):1–11. https://doi.org/10.1038/s42003-019-0297-6
Ma H, Cummins DD, Edelstein NB, Gomez J, Khan A, Llewellyn MD, Picudella T, Willsey SR, Nangia S (2017b) Modeling diversity in structures of bacterial outer membrane lipids. J Chem Theory Comput 13(2):811–824. https://doi.org/10.1021/acs.jctc.6b00856
Ma H, Irudayanathan FJ, Jiang W, Nangia S (2015) Simulating Gram-negative bacterial outer membrane: a coarse grain model. J Phys Chem B 119(46):14668–14682. https://doi.org/10.1021/acs.jpcb.5b07122
Pandit KR, Klauda JB (2012) Membrane models of E. coli containing cyclic moieties in the aliphatic lipid chain. Biochimica et Biophysica Acta (BBA)-Biomembranes 1818(5):1205–1210. https://doi.org/10.1016/j.bbamem.2012.01.009
Pothula KR, Solano CJ, Kleinekathöfer U (2016) Simulations of outer membrane channels and their permeability. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858(7):1760–1771. https://doi.org/10.1016/j.bbamem.2015.12.020
Shahane G, Ding W, Palaiokostas M, Azevedo HS, Orsi M (2019) Interaction of antimicrobial lipopeptides with bacterial lipid bilayers. J Membr Biol 252(4):317–329. https://doi.org/10.1007/s00232-019-00068-3
Khakbaz P, Klauda JB (2015) Probing the importance of lipid diversity in cell membranes via molecular simulation. Chem Phys Lipid 192:12–22. https://doi.org/10.1016/j.chemphyslip.2015.08.003
Lim JB, Klauda JB (2011) Lipid chain branching at the iso-and anteiso-positions in complex chlamydia membranes: A molecular dynamics study. Biochimica et Biophysica Acta (BBA)-Biomembranes 1808(1):323–331. https://doi.org/10.1016/j.bbamem.2010.07.036
Jin T, Patel SJ, Van Lehn RC (2021) Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators. Plos one 16(2):e0246187. https://doi.org/10.1371/journal.pone.0246187
Lee J, Patel DS, Kucharska I, Tamm LK, Im W (2017) Refinement of OprH-LPS interactions by molecular simulations. Biophys J 112(2):346–355. https://doi.org/10.1016/j.bpj.2016.12.006
Ocampo-Ibáñez ID, Liscano Y, Rivera-Sánchez SP, Oñate-Garzón J, Lugo-Guevara AD, Flórez-Elvira LJ, Lesmes MC (2020) A Novel Cecropin D-Derived Short Cationic Antimicrobial Peptide Exhibits Antibacterial Activity Against Wild-Type and Multidrug-Resistant Strains of Klebsiella pneumoniae and Pseudomonas aeruginosa. Evol Bioinforma 16:1176934320936266. https://doi.org/10.1177/1176934320936266
Alkhalifa S, Jennings MC, Granata D, Klein M, Wuest WM, Minbiole KP, Carnevale V (2020) Analysis of the Destabilization of Bacterial Membranes by Quaternary Ammonium Compounds: A Combined Experimental and Computational Study. Chembiochem 21(10):1510. https://doi.org/10.1002/cbic.201900698
Lins RD, Straatsma T (2001) Computer simulation of the rough lipopolysaccharide membrane of Pseudomonas aeruginosa. Biophys J 81(2):1037–1046. https://doi.org/10.1016/S0006-3495(01)75761-X
Yu Y, Klauda JB (2018) Modeling Pseudomonas aeruginosa inner plasma membrane in planktonic and biofilm modes. J Chem Phys 149(21):215102. https://doi.org/10.1063/1.5052629
Hwang H, Paracini N, Parks JM, Lakey JH, Gumbart JC (2018) Distribution of mechanical stress in the Escherichia coli cell envelope. Biochimica et Biophysica Acta (BBA)-Biomembranes 1860(12):2566–2575. https://doi.org/10.1016/j.bbamem.2018.09.020
Piggot TJ, Holdbrook DA, Khalid S (2013) Conformational dynamics and membrane interactions of the E coli outer membrane protein FecA: a molecular dynamics simulation study. Biochimica et Biophysica Acta (BBA)-Biomembranes 1828(2):284–293. https://doi.org/10.1016/j.bbamem.2012.08.021
Kirschner KN, Lins RD, Maass A, Soares TA (2012) A glycam-based force field for simulations of lipopolysaccharide membranes: parametrization and validation. J Chem Theory Comput 8(11):4719–4731. https://doi.org/10.1021/ct300534j
Dias RP, da Hora GC, Ramstedt M, Soares TA (2014) Outer membrane remodeling: the structural dynamics and electrostatics of rough lipopolysaccharide chemotypes. J Chem Theory Comput 10(6):2488–2497. https://doi.org/10.1021/ct500075h
Van Oosten B, Harroun TA (2016) A MARTINI extension for Pseudomonas aeruginosa PAO1 lipopolysaccharide. J Mol Graph Model 63:125–133. https://doi.org/10.1016/j.jmgm.2015.12.002
Hsu P-C, Jefferies D, Khalid S (2016) Molecular dynamics simulations predict the pathways via which pristine fullerenes penetrate bacterial membranes. J Phys Chem B 120(43):11170–11179. https://doi.org/10.1021/acs.jpcb.6b06615
Shearer J, Marzinek JK, Bond PJ, Khalid S (2020) Molecular dynamics simulations of bacterial outer membrane lipid extraction: Adequate sampling? J Chem Phys 153(4):044122. https://doi.org/10.1063/5.0017734
Lee J, Patel DS, Ståhle J, Park S-J, Kern NR, Kim S, Lee J, Cheng X, Valvano MA, Holst O (2018) CHARMM-GUI membrane builder for complex biological membrane simulations with glycolipids and lipoglycans. J Chem Theory Comput 15(1):775–786. https://doi.org/10.1021/acs.jctc.8b01066
Wu, E. L.; Cheng, X.; Jo, S.; Rui, H.; Song, K. C.; Dávila‐Contreras, E. M.; Qi, Y.; Lee, J.; Monje‐Galvan, V.; Venable, R. M., CHARMM‐GUI membrane builder toward realistic biological membrane simulations. Wiley Online Library: 2014. https://doi.org/10.1002/jcc.23702
Khalid S, Berglund NA, Holdbrook DA, Leung YM, Parkin J (2015) The membranes of Gram-negative bacteria: progress in molecular modelling and simulation. Biochem Soc Trans 43(2):162–167. https://doi.org/10.1042/bst20140262
Patel DS, Qi Y, Im W (2017) Modeling and simulation of bacterial outer membranes and interactions with membrane proteins. Curr Opin Struct Biol 43:131–140. https://doi.org/10.1016/j.sbi.2017.01.003
Chakraborty, A.; Kobzev, E.; Chan, J.; de Zoysa, G. H.; Sarojini, V.; Piggot, T. J.; Allison, J. R., Molecular Dynamics Simulation of the Interaction of Two Linear Battacin Analogs with Model Gram-Positive and Gram-Negative Bacterial Cell Membranes. ACS Omega 2020. https://doi.org/10.1021/acsomega.0c04752
Kim S, Patel DS, Park S, Slusky J, Klauda JB, Widmalm G, Im W (2016) Bilayer properties of lipid A from various Gram-negative bacteria. Biophys J 111(8):1750–1760. https://doi.org/10.1016/j.bpj.2016.09.001
Goossens K, De Winter H (2018) Molecular dynamics simulations of membrane proteins: An overview. J Chem Inf Model 58(11):2193–2202. https://doi.org/10.1021/acs.jcim.8b00639
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The authors acknowledge support from the Austrian Institute for Technology. A.B.C. acknowledges AINSE for an Honours scholarship.
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Carey, A.B., Ashenden, A. & Köper, I. Model architectures for bacterial membranes. Biophys Rev 14, 111–143 (2022). https://doi.org/10.1007/s12551-021-00913-7
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DOI: https://doi.org/10.1007/s12551-021-00913-7