Theoretical Insights into the Interactions between Star-Shaped Antimicrobial Polypeptides and Bacterial Membranes

Langmuir ◽  
2018 ◽  
Vol 34 (44) ◽  
pp. 13438-13448 ◽  
Author(s):  
Yunhan Zhang ◽  
Tongwei Chen ◽  
Zhimeng Pan ◽  
Xianbao Sun ◽  
Xue Yin ◽  
...  
Keyword(s):  
Bacterial Membranes ◽  
Antimicrobial Polypeptides

scholarly journals How Insertion of a Single Tryptophan in the N-Terminus of a Cecropin A-Melittin Hybrid Peptide Changes Its Antimicrobial and Biophysical Profile

Membranes ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 48
Author(s):  
Ana Rita Ferreira ◽  
Cátia Teixeira ◽  
Carla F. Sousa ◽  
Lucinda J. Bessa ◽  
Paula Gomes ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Bacterial Infections ◽  
Electron System ◽  
Bacterial Membranes ◽  
Highly Active ◽  
Large Unilamellar Vesicles ◽  
Biophysical Profile ◽  
N Terminus ◽  
Lysine Residues ◽  
Preferential Location

In the era of antibiotic resistance, there is an urgent need for efficient antibiotic therapies to fight bacterial infections. Cationic antimicrobial peptides (CAMP) are promising lead compounds given their membrane-targeted mechanism of action, and high affinity towards the anionic composition of bacterial membranes. We present a new CAMP, W-BP100, derived from the highly active BP100, holding an additional tryptophan at the N-terminus. W-BP100 showed a broader antibacterial activity, demonstrating a potent activity against Gram-positive strains. Revealing a high partition constant towards anionic over zwitterionic large unilamellar vesicles and inducing membrane saturation at a high peptide/lipid ratio, W-BP100 has a preferential location for hydrophobic environments. Contrary to BP100, almost no aggregation of anionic vesicles is observed around saturation conditions and at higher concentrations no aggregation is observed. With these results, it is possible to state that with the incorporation of a single tryptophan to the N-terminus, a highly active peptide was obtained due to the π–electron system of tryptophan, resulting in negatively charged clouds, that participate in cation–π interactions with lysine residues. Furthermore, we propose that W-BP100 action can be achieved by electrostatic interactions followed by peptide translocation.

scholarly journals A polymeric approach toward resistance-resistant antimicrobial agent with dual-selective mechanisms of action

2021 ◽  
Vol 7 (5) ◽  
pp. eabc9917
Author(s):  
Silei Bai ◽  
Jianxue Wang ◽  
Kailing Yang ◽  
Cailing Zhou ◽  
Yangfan Xu ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mechanisms Of Action ◽  
Model Systems ◽  
General Strategy ◽  
Antimicrobial Polymers ◽  
Bacterial Dna ◽  
Bacterial Membranes ◽  
Severe Infections ◽  
Multiple Drugs ◽  
Resistance Rates

Antibiotic resistance is now a major threat to human health, and one approach to combating this threat is to develop resistance-resistant antibiotics. Synthetic antimicrobial polymers are generally resistance resistant, having good activity with low resistance rates but usually with low therapeutic indices. Here, we report our solution to this problem by introducing dual-selective mechanisms of action to a short amidine-rich polymer, which can simultaneously disrupt bacterial membranes and bind to bacterial DNA. The oligoamidine shows unobservable resistance generation but high therapeutic indices against many bacterial types, such as ESKAPE strains and clinical isolates resistant to multiple drugs, including colistin. The oligomer exhibited excellent effectiveness in various model systems, killing extracellular or intracellular bacteria in the presence of mammalian cells, removing all bacteria from Caenorhabditis elegans, and rescuing mice with severe infections. This “dual mechanisms of action” approach may be a general strategy for future development of antimicrobial polymers.

scholarly journals Linearized esculentin-2EM shows pH dependent antibacterial activity with an alkaline optimum

2021 ◽  
Author(s):  
Erum Malik ◽  
David A. Phoenix ◽  
Timothy J. Snape ◽  
Frederick Harris ◽  
Jaipaul Singh ◽  
...  
Keyword(s):  
Helical Structure ◽  
Food Preservation ◽  
Forming Process ◽  
Gram Positive ◽  
Gram Negative ◽  
Bacterial Membranes ◽  
Gram Positive Bacteria ◽  
Alkaline Conditions ◽  
Ph Dependent ◽  
Gram Negative Organisms

AbstractHere the hypothesis that linearized esculentin 2EM (E2EM-lin) from Glandirana emeljanovi possesses pH dependent activity is investigated. The peptide showed weak activity against Gram-negative bacteria (MLCs ≥ 75.0 μM) but potent efficacy towards Gram-positive bacteria (MLCs ≤ 6.25 μM). E2EM-lin adopted an α-helical structure in the presence of bacterial membranes that increased as pH was increased from 6 to 8 (↑ 15.5–26.9%), whilst similar increases in pH enhanced the ability of the peptide to penetrate (↑ 2.3–5.1 mN m−1) and lyse (↑ 15.1–32.5%) these membranes. Theoretical analysis predicted that this membranolytic mechanism involved a tilted segment, that increased along the α-helical long axis of E2EM-lin (1–23) in the N → C direction, with −  < µH > increasing overall from circa − 0.8 to − 0.3. In combination, these data showed that E2EM-lin killed bacteria via novel mechanisms that were enhanced by alkaline conditions and involved the formation of tilted and membranolytic, α-helical structure. The preference of E2EM-lin for Gram-positive bacteria over Gram-negative organisms was primarily driven by the superior ability of phosphatidylglycerol to induce α-helical structure in the peptide as compared to phosphatidylethanolamine. These data were used to generate a novel pore-forming model for the membranolytic activity of E2EM-lin, which would appear to be the first, major reported instance of pH dependent AMPs with alkaline optima using tilted structure to drive a pore-forming process. It is proposed that E2EM-lin has the potential for development to serve purposes ranging from therapeutic usage, such as chronic wound disinfection, to food preservation by killing food spoilage organisms.

scholarly journals On the Wireless Microwave Sensing of Bacterial Membrane Potential in Microfluidic-Actuated Platforms

Sensors ◽  
2021 ◽  
Vol 21 (10) ◽  
pp. 3420
Author(s):  
Marc Jofre ◽  
Lluís Jofre ◽  
Luis Jofre-Roca
Keyword(s):  
Membrane Potential ◽  
Living Cells ◽  
Membrane Potentials ◽  
Electromagnetic Properties ◽  
Bacterial Membrane ◽  
Microfluidic Platforms ◽  
Bacterial Membranes ◽  
Wireless Monitoring ◽  
Bacterial Dynamics ◽  
Engineered Systems

The investigation of the electromagnetic properties of biological particles in microfluidic platforms may enable microwave wireless monitoring and interaction with the functional activity of microorganisms. Of high relevance are the action and membrane potentials as they are some of the most important parameters of living cells. In particular, the complex mechanisms of a cell’s action potential are comparable to the dynamics of bacterial membranes, and consequently focusing on the latter provides a simplified framework for advancing the current techniques and knowledge of general bacterial dynamics. In this work, we provide a theoretical analysis and experimental results on the microwave detection of microorganisms within a microfluidic-based platform for sensing the membrane potential of bacteria. The results further advance the state of microwave bacteria sensing and microfluidic control and their implications for measuring and interacting with cells and their membrane potentials, which is of great importance for developing new biotechnologically engineered systems and solutions.

scholarly journals Long-term effects of the proline-rich antimicrobial peptide Oncocin112 on the Escherichia coli translation machinery

2020 ◽  
Vol 295 (38) ◽  
pp. 13314-13325
Author(s):  
Yanyu Zhu ◽  
James C. Weisshaar ◽  
Mainak Mustafi
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Peptides ◽  
Binding Site ◽  
Elongation Factor ◽  
Microscopy Study ◽  
Single Step ◽  
Long Term Effects ◽  
Bacterial Membranes

Proline-rich antimicrobial peptides (PrAMPs) are cationic antimicrobial peptides unusual for their ability to penetrate bacterial membranes and kill cells without causing membrane permeabilization. Structural studies show that many such PrAMPs bind deep in the peptide exit channel of the ribosome, near the peptidyl transfer center. Biochemical studies of the particular synthetic PrAMP oncocin112 (Onc112) suggest that on reaching the cytoplasm, the peptide occupies its binding site prior to the transition from initiation to the elongation phase of translation, thus blocking further initiation events. We present a superresolution fluorescence microscopy study of the long-term effects of Onc112 on ribosome, elongation factor-Tu (EF-Tu), and DNA spatial distributions and diffusive properties in intact Escherichia coli cells. The new data corroborate earlier mechanistic inferences from studies in vitro. Comparisons with the diffusive behavior induced by the ribosome-binding antibiotics chloramphenicol and kasugamycin show how the specific location of each agent's ribosomal binding site affects the long-term distribution of ribosomal species between 30S and 50S subunits versus 70S polysomes. Analysis of the single-step displacements from ribosome and EF-Tu diffusive trajectories before and after Onc112 treatment suggests that the act of codon testing of noncognate ternary complexes (TCs) at the ribosomal A-site enhances the dissociation rate of such TCs from their L7/L12 tethers. Testing and rejection of noncognate TCs on a sub-ms timescale is essential to enable incorporation of the rare cognate amino acids into the growing peptide chain at a rate of ∼20 aa/s.

scholarly journals Acylation of SC4 dodecapeptide increases bactericidal potency against Gram-positive bacteria, including drug-resistant strains

2004 ◽  
Vol 378 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Nathan A. LOCKWOOD ◽  
Judith R. HASEMAN ◽  
Matthew V. TIRRELL ◽  
Kevin H. MAYO
Keyword(s):  
Fatty Acid ◽  
Fluorescence Spectroscopy ◽  
Bactericidal Activity ◽  
Bacterial Cell ◽  
Membrane Surface ◽  
Peptide Amphiphiles ◽  
Helical Conformation ◽  
Gram Positive ◽  
Bacterial Membranes ◽  
Bactericidal Activities

We have conjugated dodecyl and octadecyl fatty acids to the N-terminus of SC4, a potently bactericidal, helix-forming peptide 12-mer (KLFKRHLKWKII), and examined the bactericidal activities of the resultant SC4 ‘peptide-amphiphile’ molecules. SC4 peptide-amphiphiles showed up to a 30-fold increase in bactericidal activity against Gram-positive strains (Staphylococcus aureus, Streptococcus pyogenes and Bacillus anthracis), including S. aureus strains resistant to conventional antibiotics, but little or no increase in bactericidal activity against Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Fatty acid conjugation improved endotoxin (lipopolysaccharide) neutralization by 3- to 6-fold. Although acylation somewhat increased lysis of human erythrocytes, it did not increase lysis of endothelial cells, and the haemolytic effects occurred at concentrations 10- to 100-fold higher than those required for bacterial cell lysis. For insight into the mechanism of action of SC4 peptide-amphiphiles, CD, NMR and fluorescence spectroscopy studies were performed in micelle and liposome models of eukaryotic and bacterial cell membranes. CD indicated that SC4 peptide-amphiphiles had the strongest helical tendencies in liposomes mimicking bacterial membranes, and strong membrane integration of the SC4 peptide-amphiphiles was observed using tryptophan fluorescence spectroscopy under these conditions; results that correlated with the increased bactericidal activities of SC4 peptide-amphiphiles. NMR structural analysis in micelles demonstrated that the two-thirds of the peptide closest to the fatty acid tail exhibited a helical conformation, with the positively-charged side of the amphipathic helix interacting more with the model membrane surface. These results indicate that conjugation of a fatty acid chain to the SC4 peptide enhances membrane interactions, stabilizes helical structure in the membrane-bound state and increases bactericidal potency.

Structural Characterization of Complex Bacterial Glycolipids by Fourier Transform Mass Spectrometry

2005 ◽  
Vol 11 (5) ◽  
pp. 535-546 ◽  
Author(s):  
Anna Kondakov ◽  
Buko Lindner
Keyword(s):  
Mass Spectrometry ◽  
Fourier Transform ◽  
Structural Information ◽  
Adaptive Immune System ◽  
Ion Cyclotron Resonance ◽  
Bacterial Membranes ◽  
Multiphoton Dissociation ◽  
The One ◽  
And Function

Bacterial glycolipids are complex amphiphilic molecules which are, on the one hand, of utmost importance for the organization and function of bacterial membranes and which, on the other hand, play a major role in the activation of cells of the innate and adaptive immune system of the host. Already small alterations to their chemical structure may influence the biological activity tremendously. Due to their intrinsic biological heterogeneity [number and type of fatty acids, saccharide structures and substitution with for example, phosphate ( P), 2-aminoethyl-(pyro)phosphate groups ( P-Etn) or 4-amino-4-deoxyarabinose (Ara4N)], separation of the different components are a prerequisite for unequivocal chemical and nuclear magnetic resonance structural analyses. In this contribution, the structural information which can be obtained from heterogenous samples of glycolipids by Fourier transform (FT) ion cyclotron resonance mass spectrometric methods is described. By means of recently analysed complex biological samples, the possibilities of high-resolution electrospray ionization FT-MS are demonstrated. Capillary skimmer dissociation, as well as tandem mass spectrometry (MS/MS) analysis utilizing collision-induced dissociation and infrared multiphoton dissociation, are compared and their advantages in providing structural information of diagnostic importance are discussed.

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