Computer Simulation of the Rough Lipopolysaccharide Membrane of Pseudomonas aeruginosa

Lins, Roberto D.; Straatsma, Tjerk P.

doi:10.1016/s0006-3495(01)75761-x

Cited by 109 publications

(114 citation statements)

References 39 publications

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“…In contrast, amphiphilic neamine derivatives, which are more flexible than colistin, induced a large increase in membrane fluidity, leading to a facilitated insertion in the lipid bilayer. This extends the results published by others (58,59) who suggested a critical role for the flexibility of the molecule and disordering, especially against colistin-resistant strains. These are characterized by changes in lipid A structures leading to modifications of hydrophobicity and molecular packing of LPS (60)(61)(62)(63).…”

Section: Discussionsupporting

confidence: 90%

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

Sautrey

Zimmermann

Deleu

et al. 2014

Antimicrob Agents Chemother

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The development of novel antimicrobial agents is urgently required to curb the widespread emergence of multidrug-resistant bacteria like colistin-resistant Pseudomonas aeruginosa. We previously synthesized a series of amphiphilic neamine derivatives active against bacterial membranes, among which 3=,6-di-O-[(2؆-naphthyl)propyl]neamine (3=,6-di2NP), 3=,6-di-O-[(2؆-naphthyl)butyl]neamine (3=,6-di2NB), and 3=,6-di-O-nonylneamine (3=,6-diNn) showed high levels of activity and low levels of cytotoxicity (L. Zimmermann et al., J. Med. Chem. 56:7691-7705, 2013). We have now further characterized the activity of these derivatives against colistin-resistant P. aeruginosa and studied their mode of action; specifically, we characterized their ability to interact with lipopolysaccharide (LPS) and to alter the bacterial outer membrane (OM). The three amphiphilic neamine derivatives were active against clinical colistin-resistant strains (MICs, about 2 to 8 g/ml), The most active one (3=,6-diNn) was bactericidal at its MIC and inhibited biofilm formation at 2-fold its MIC. They cooperatively bound to LPSs, increasing the outer membrane permeability. Grafting long and linear alkyl chains (nonyl) optimized binding to LPS and outer membrane permeabilization. The effects of amphiphilic neamine derivatives on LPS micelles suggest changes in the cross-bridging of lipopolysaccharides and disordering in the hydrophobic core of the micelles. The molecular shape of the 3=,6-dialkyl neamine derivatives induced by the nature of the grafted hydrophobic moieties (naphthylalkyl instead of alkyl) and the flexibility of the hydrophobic moiety are critical for their fluidifying effect and their ability to displace cations bridging LPS. Results from this work could be exploited for the development of new amphiphilic neamine derivatives active against colistin-resistant P. aeruginosa.

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Section: Discussionsupporting

confidence: 90%

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

Sautrey

Zimmermann

Deleu

et al. 2014

Antimicrob Agents Chemother

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“…The structures of the R core and O antigen (which should not exist in this strain) chosen for the modeling were not described either. Some of these deficiencies are not present in the molecular dynamic simulation of the P. aeruginosa OM bilayer (380,610). Thus, the GlcN-GlcN backbone of all LPS molecules become oriented in a similar direction, and, most importantly, the divalent cation (Ca 2ϩ was used in this simulation) binds four neighboring LPS molecules by coordinating with phosphate groups at the 1 and 4Ј positions.…”

Section: What Makes the Lps Leaflet An Effectivementioning

confidence: 99%

Molecular Basis of Bacterial Outer Membrane Permeability Revisited

Nikaido

2003

Microbiol Mol Biol Rev

3,780

3,800

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Gram-negative bacteria characteristically are surrounded by an additional membrane layer, the outer membrane. Although outer membrane components often play important roles in the interaction of symbiotic or pathogenic bacteria with their host organisms, the major role of this membrane must usually be to serve as a permeability barrier to prevent the entry of noxious compounds and at the same time to allow the influx of nutrient molecules. This review summarizes the development in the field since our previous review (H. Nikaido and M. Vaara, Microbiol. Rev. 49:1-32, 1985) was published. With the discovery of protein channels, structural knowledge enables us to understand in molecular detail how porins, specific channels, TonB-linked receptors, and other proteins function. We are now beginning to see how the export of large proteins occurs across the outer membrane. With our knowledge of the lipopolysaccharide-phospholipid asymmetric bilayer of the outer membrane, we are finally beginning to understand how this bilayer can retard the entry of lipophilic compounds, owing to our increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopolysaccharide structure is modified by environmental conditions

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“…While many studies have focused on the amount of metal bound/adsorbed by cells and the development of bulk partitioning models (5), questions such as the mechanism of adsorption (20), the specific binding sites (9), and the impacts of different environmental conditions on adsorption (31) have received less attention. Such information is crucial for the development of models to predict the behavior of metals under a range of conditions and to determine the potential uses of these organisms for environmental remediation (11,15).Pseudomonas aeruginosa is a ubiquitous, well-characterized microorganism used in many metal-binding investigations (10). Suggested metal ion binding sites in P. aeruginosa include the phosphate and carboxyl groups in the peptidoglycan (29) and charged groups in both the core oligosaccharide region and the O-antigenic side chains that make up its LPS (14, 28).…”

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confidence: 99%

Mechanisms of Cation Exchange by Pseudomonas aeruginosa PAO1 and PAO1 wbpL , a Strain with a Truncated Lipopolysaccharide

Shephard

McQuillan

Bremer

2008

Appl Environ Microbiol

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The ability of bacterial cells to sequester cations is well recognized, despite the fact that the specific binding sites and mechanistic details of the process are not well understood. To address these questions, the cationexchange behavior of Pseudomonas aeruginosa PAO1 cells with a truncated lipopolysaccharide (LPS) (PAO1 wbpL) and cells further modified by growth in a magnesium-deficient medium (PAO1 wbpL ؊ Mg 2؉ ) were compared with that of wild-type P. aeruginosa PAO1 cells. P. aeruginosa PAO1 cells had a negative surface charge (zeta potential) between pH 11 and 2.2, due to carboxylate groups present in the B-band LPS. The net charge on PAO1 wbpL cells was increasingly positive below pH 3.5, due to the influence of NH 3 ؉ groups in the core LPS. The zeta potentials of these cells were also measured in Na ؉ , Ca 2؉ , and La 3؉ electrolytes. Cells in the La 3؉ electrolyte had a positive zeta potential at all pH values tested. Growing P. aeruginosa PAO1 wbpL in magnesium-deficient medium (PAO1 wbpL ؊ Mg 2؉ ) resulted in an increase in its zeta potential in the pH range from 3.0 to 6.5. In cation-exchange experiments carried out at neutral pH with either P. aeruginosa PAO1 or PAO1 wbpL, the concentration of bound Ca 2؉ was found to decrease as the pH was reduced from 7.0 to 3.5. At pH 3.5, the bound Mg 2؉ concentration decreased sharply, revealing the activity of surface sites for cation exchange and their pH dependence. Infrared spectroscopy of attached biofilms suggested that carboxylate and phosphomonoester functional groups within the core LPS are involved in cation exchange.The ability of microbial cells to sequester metal ions from aqueous environments is important for microbial growth and biogeochemical processes, such as mineral formation/dissolution, metal transport, and the bioremediation of metal-contaminated sites (1). The external surfaces of gram-negative bacteria are comprised of phospholipids, lipoproteins, lipopolysaccharides (LPS), and proteins. These polymers contain carboxylic acids and phosphate esters, which are primarily responsible for the cells having a net negative charge (at neutral pH), and associated cations, which are retained even after thorough washing with water due to the electroneutrality condition (6, 12, 31). These cations may undergo cation exchange with the introduction of electrolyte solutions containing different cations. While many studies have focused on the amount of metal bound/adsorbed by cells and the development of bulk partitioning models (5), questions such as the mechanism of adsorption (20), the specific binding sites (9), and the impacts of different environmental conditions on adsorption (31) have received less attention. Such information is crucial for the development of models to predict the behavior of metals under a range of conditions and to determine the potential uses of these organisms for environmental remediation (11,15).Pseudomonas aeruginosa is a ubiquitous, well-characterized microorganism used in many metal-binding investigations (10). Suggest...

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Computer Simulation of the Rough Lipopolysaccharide Membrane of Pseudomonas aeruginosa

Cited by 109 publications

References 39 publications

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas aeruginosa and Their Interactions with Lipopolysaccharides

Molecular Basis of Bacterial Outer Membrane Permeability Revisited

Mechanisms of Cation Exchange by Pseudomonas aeruginosa PAO1 and PAO1 wbpL , a Strain with a Truncated Lipopolysaccharide

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