Role of the Conformational Rigidity in the Design of Biomimetic Antimicrobial Compounds

Ivankin, Andrey; Livne, Liran; Mor, Amram; Caputo, Gregory A.; DeGrado, William F.; Meron, Mati; Lin, Binhua; Gidalevitz, David

doi:10.1002/anie.201003104

Cited by 48 publications

(56 citation statements)

References 20 publications

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“…There is also a broad out-of-plane peak ( Q xy = 1.343 Å –1 ) at 3 mM m –1 that shifts to higher values of Q xy as the surface pressure increases, eventually merging with the in-plane peak at Q xy = 1.498 at 45 mN m –1 (Figures 5 and 6a). As shown in Table 3, the unit cell dimensions vary with surface pressure but generally a ≈ 4.33 Å, b ≈ 4.25 Å, and γ ≈ 81.3°, which confirms the oblique hexagonal packing ( a ≠ b , γ ≠ 90°) and corresponds to an area per unit cell, A cell ≈ 18.2 Å 2 , consistent with literature values for lipid hydrocarbon tails of DPPG, lipid A, and ReLPS 23,24,29,41 and gives an area per LPS molecule of 109 Å 2 . Figure 6b shows the GIXD data integrated along Q xy , and the peak at Q z = 0 is the Vineyard–Yoneda peak, which results from interference by the diffracted X-rays from the Bragg rod and reflected rays at the interface.…”

Section: Resultssupporting

confidence: 87%

“…These models have been used to study the effect of calcium ion binding 24,26 or membrane disruption by antimicrobial agents. 23,29,30 The current models reflect only the outer membrane surface of deep rough mutants of Gram-negative bacteria, accounting for only a small portion of known bacterial strains. Most Gram-negative bacteria contain smooth LPS, which due to the long polysaccharide chain are very water-soluble when purified.…”

Section: Introductionmentioning

confidence: 99%

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Structural Characterization of a Model Gram-Negative Bacterial Surface Using Lipopolysaccharides from Rough Strains of Escherichia coli

et al. 2013

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Lipopolysaccharides (LPS) make up approximately 75% of the Gram-negative bacterial outer membrane (OM) surface, but because of the complexity of the molecule, there are very few model OMs that include LPS. The LPS molecule consists of lipid A, which anchors the LPS within the OM, a core polysaccharide region, and a variable O-antigen polysaccharide chain. In this work we used RcLPS (consisting of lipid A plus the first seven sugars of the core polysaccharide) from a rough strain of Escherichia coli to form stable monolayers of LPS at the air–liquid interface. The vertical structure RcLPS monolayers were characterized using neutron and X-ray reflectometry, while the lateral structure was investigated using grazing incidence X-ray diffraction and Brewster angle microscopy. It was found that RcLPS monolayers at surface pressures of 20 mN m–1 and above are resolved as hydrocarbon tails, an inner headgroup, and an outer headgroup of polysaccharide with increasing solvation from tails to outer headgroups. The lateral organization of the hydrocarbon lipid chains displays an oblique hexagonal unit cell at all surface pressures, with only the chain tilt angle changing with surface pressure. This is in contrast to lipid A, which displays hexagonal or, above 20 mN m–1, distorted hexagonal packing. This work provides the first complete structural analysis of a realistic E. coli OM surface model.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Structural Characterization of a Model Gram-Negative Bacterial Surface Using Lipopolysaccharides from Rough Strains of Escherichia coli

et al. 2013

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“…This approach has been successfully used in conjunction with liquid surface X-ray scattering to study bacterial membrane lysis by human antimicrobial peptide LL-37,[60] protegrin-1[57, 62] gramicidin[63] and SMAP-29[61] antimicrobial peptides as well as by peptide mimics. [44, 59, 64, 65]…”

Section: Introductionmentioning

confidence: 99%

Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes

Andreev

Bianchi

Laursen

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A promising class of potential new antibiotics are the antimicrobial peptides or their synthetic mimics. Herein we assess the effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial α-peptide–β-peptoid chimeras. Two separate Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) and lipopolysaccharide Kdo2-lipid A were applied to model the outer membranes of Gram-positive and Gram-negative bacteria, respectively. We report the results of the measurements using an array of techniques, including high-resolution synchrotron surface X-ray scattering, epifluorescence microscopy, and in vitro antimicrobial activity to study the molecular mechanisms of peptidomimetic interaction with bacterial membranes. We found guanidino group-containing chimeras to exhibit greater disruptive activity on DPPG monolayers than the amino group-containing analogues. However, this effect was not observed for lipopolysaccharide monolayers where the difference was negligible. Furthermore, the addition of the nitrobenzoxadiazole fluorophore did not reduce the insertion activity of these antimicrobials into both model membrane systems examined, which may be useful for future cellular localization studies.

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“…10,11 Indeed, a pre-organized secondary structure seems not required for bacterial killing; 5 instead, oligomers with a strong propensity for helical conformation or conformational rigidity may lead to high hemolytic activity. 4,12 Potent antimicrobial activity may actually require the presence of flexible, or even random coiled backbones, where side groups are segregated into hydrophobic and cationic regions upon interaction with bacterial membranes, 5,12 even if the amphiphilic conformation is irregular and non-helical.…”

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confidence: 99%

Identification of γ-AApeptides with potent and broad-spectrum antimicrobial activity

et al. 2011

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Role of the Conformational Rigidity in the Design of Biomimetic Antimicrobial Compounds

Cited by 48 publications

References 20 publications

Structural Characterization of a Model Gram-Negative Bacterial Surface Using Lipopolysaccharides from Rough Strains of Escherichia coli

Structural Characterization of a Model Gram-Negative Bacterial Surface Using Lipopolysaccharides from Rough Strains of Escherichia coli

Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes

Identification of γ-AApeptides with potent and broad-spectrum antimicrobial activity

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