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A molecular dynamics and circular dichroism study of a novel synthetic antimicrobial peptide  [PDF]
Natalia P. Rodina,Anna N. Yudenko,Ivan N. Terterov,Igor E. Eliseev
Quantitative Biology , 2013, DOI: 10.1088/1742-6596/461/1/012015
Abstract: Antimicrobial peptides are a class of small, usually positively charged amphiphilic peptides that are used by the innate immune system to combat bacterial infection in multicellular eukaryotes. Antimicrobial peptides are known for their broad-spectrum antimicrobial activity and thus can be used as a basis for a development of new antibiotics against multidrug-resistant bacteria. The most challengeous task on the way to a therapeutic use of antimicrobial peptides is a rational design of new peptides with enhanced activity and reduced toxicity. Here we report a molecular dynamics and circular dichroism study of a novel synthetic antimicrobial peptide D51. This peptide was earlier designed by Loose et al. using a linguistic model of natural antimicrobial peptides. Molecular dynamics simulation of the peptide folding in explicit solvent shows fast formation of two antiparallel beta strands connected by a beta-turn that is confirmed by circular dichroism measurements. Obtained from simulation amphipatic conformation of the peptide is analysed and possible mechanism of its interaction with bacterial membranes together with ways to enhance its antibacterial activity are suggested.
The Application of Biophysical Techniques to Study Antimicrobial Peptides
Inês M. Torcato,Miguel A. R. B. Castanho,Sónia T. Henriques
Spectroscopy: An International Journal , 2012, DOI: 10.1155/2012/460702
Abstract: The increasing bacteria resistance to conventional antibiotics has led to the need for alternative therapies. Being part of the human innate defence system and with a broad spectrum of activity against bacteria, viruses, protozoa, and cancer cells, antimicrobial peptides (AMPs) are a very promising alternative. The mechanism of action of AMPs seems to broadly correlate with their ability to target the bacterial cell membrane. To understand and improve their effect, it is of major importance to unravel their mechanism of action and, in particular, to understand the peptide-membrane binding. Several biophysical techniques such as fluorescence spectroscopy, circular dichroism, zeta potential determination, and atomic force microscopy can be used to achieve this goal. Characteristics of AMPs-membranes interactions and the use of these biophysical techniques will be discussed.
C- and N-truncated antimicrobial peptides from LFampin 265 - 284: Biophysical versus microbiology results  [cached]
Ad?o Regina,Nazmi Kamran,Bolscher Jan,Bastos Margarida
Journal of Pharmacy and Bioallied Sciences , 2011,
Abstract: Lactoferrin is a glycoprotein with two globular lobes, each having two domains. Since the discovery of its antimicrobial properties, efforts have been made to find peptides derived from this protein showing antimicrobial properties. Most peptides initially studied were derived from Lactoferricin B, obtained from the protein by digestion with pepsin. More recently, a new family of antimicrobial peptides (AMPs) derived from Lactoferrin was discovered by Bolcher et al, and named Lactoferrampin (LFampin). The original sequence of LFampin contained residues 268 - 284 from the N1 domain of Lactoferrin. From this peptide, the Bolscher′s group synthesized a collection of peptides obtained by extension and / or truncation at the C or N-terminal sides, in order to unravel the main structural features responsible for antimicrobial action. Here, we present results for three of these peptides, namely LFampin 265 - 284, LFampin 265 - 280, and LFampin 270 - 284. The peptides were tested against bacteria (E. coli and S. sanguinis), fungi (C. albicans), and model membranes of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DMPG), and their mixtures at a ratio of 3 : 1 (DMPC : DMPG (3 : 1)). The ability to adopt a helical conformation was followed by a circular dichroism (CD), and the perturbation of the gel to the liquid-crystalline phase transition of the membrane was characterized by differential scanning calorimetry (DSC). Distinct behavior was observed in the three peptides, both from the microbiology and model membrane studies, with the biophysical results showing excellent correlation with the microbiology activity studies. LFampin 265 - 284 was the most active peptide toward the tested microorganisms, and in the biophysical studies it showed the highest ability to form an a-helix and the strongest interaction with model membranes, followed by LFampin 265 - 280. LFampin 270 - 284 was inactive, showing marginal secondary structure and no interaction with the pathogen model membranes.
Generation of novel cationic antimicrobial peptides from natural non-antimicrobial sequences by acid-amide substitution
Satoshi Ueno, Masaomi Minaba, Yuji Nishiuchi, Misako Taichi, Yasushi Tamada, Toshimasa Yamazaki, Yusuke Kato
Annals of Clinical Microbiology and Antimicrobials , 2011, DOI: 10.1186/1476-0711-10-11
Abstract: The pro-regions of nematode cecropin P1-P3 (P1P-P3P) were selected as parent sequences. P1P-P3P and their acid-amide-substituted mutants (NP1P-NP3P) were chemically synthesized. Bactericidal and membrane-disruptive activities of these peptides were evaluated. Conformational changes were estimated from far-ultraviolet circular dichroism (CD) spectra.NP1P-NP3P acquired potent bactericidal activities via membrane-disruption although P1P-P3P were not antimicrobial. Far-ultraviolet CD spectra of NP1P-NP3P were similar to those of their parent peptides P1P-P3P, suggesting that NP1P-NP3P acquire microbicidal activity without remarkable conformational changes. NP1P-NP3P killed bacteria in almost parallel fashion with their membrane-disruptive activities, suggesting that the mode of action of those peptides was membrane-disruption. Interestingly, membrane-disruptive activity of NP1P-NP3P were highly diversified against acidic liposomes, indicating that the acid-amide-substituted nematode cecropin pro-region was expected to be a unique and promising skeleton for novel synthetic CAMPs with diversified membrane-discriminative properties.The acid-amide substitution successfully generated some novel CAMPs in our trial study. These novel CAMPs were derived from natural non-antimicrobial sequences, and their sequences were completely distinct from any categories of known CAMPs, suggesting that such mutated natural sequences could be a promising source of novel skeletons of CAMPs.Cationic antimicrobial peptides (CAMPs) are well recognized to be promising as novel antimicrobial and antitumor agents. Natural CAMPs are structurally much diverse (e.g., linear cationic α-helical CAMPs, those enriched for specific amino acids, and those containing disulphide bonds and stable β-sheets) [1]. Because each category exhibits characteristic antimicrobial properties, numerous researchers have tried to identify novel skeletons of natural CAMPs from various organisms over the last two decades. Man
Structural and antimicrobial properties of human pre-elafin/trappin-2 and derived peptides against Pseudomonas aeruginosa
Audrey Bellemare, Nathalie Vernoux, Sébastien Morin, Stéphane M Gagné, Yves Bourbonnais
BMC Microbiology , 2010, DOI: 10.1186/1471-2180-10-253
Abstract: We show here that the cementoin domain adopts an α-helical conformation both by circular dichroism and nuclear magnetic resonance analyses in the presence of membrane mimetics, a characteristic shared with a large number of linear polycationic antimicrobial peptides. However, pre-elafin/trappin-2 and its domains display only weak lytic properties, as assessed by scanning electron micrography, outer and inner membrane depolarization studies with P. aeruginosa and leakage of liposome-entrapped calcein. Confocal microscopy of fluorescein-labeled pre-elafin/trappin-2 suggests that this protein possesses the ability to translocate across membranes. This correlates with the finding that pre-elafin/trappin-2 and elafin bind to DNA in vitro and attenuate the expression of some P. aeruginosa virulence factors, namely the biofilm formation and the secretion of pyoverdine.The N-terminal cementoin domain adopts α-helical secondary structures in a membrane mimetic environment, which is common in antimicrobial peptides. However, unlike numerous linear polycationic antimicrobial peptides, membrane disruption does not appear to be the main function of either cementoin, elafin or full-length pre-elafin/trappin-2 against P. aeruginosa. Our results rather suggest that pre-elafin/trappin-2 and elafin, but not cementoin, possess the ability to modulate the expression of some P.aeruginosa virulence factors, possibly through acting on intracellular targets.Pseudomonas aeruginosa is a Gram-negative bacterium that rarely causes serious infections in healthy individuals. It is, however, the prevalent opportunist pathogen encountered in nosocomial infections and the major etiologic agent responsible for the morbidity, clinical deterioration and early mortality associated with patients suffering from cystic fibrosis (CF) [1-5]. A plethora of virulence factors expressed by P. aeruginosa is associated with acute and chronic infections [6]. Perhaps the most dramatic change that characterizes P. a
Structural Characterization of de Novo Designed L5K5W Model Peptide Isomers with Potent Antimicrobial and Varied Hemolytic Activities  [PDF]
Seo-Jin Kim,Jae-Seok Kim,Yoo-Sup Lee,Dae-Won Sim,Sung-Hee Lee,Young-Yil Bahk,Kwang-Ho Lee,Eun-Hee Kim,Sung-Jean Park,Bong-Jin Lee,Hyung-Sik Won
Molecules , 2013, DOI: 10.3390/molecules18010859
Abstract: In an effort to develop short antimicrobial peptides with simple amino acid compositions, we generated a series of undecapeptide isomers having the L 5K 5W formula. Amino acid sequences were designed to be perfectly amphipathic when folded into a helical conformation by converging leucines onto one side and lysines onto the other side of the helical axis. The single tryptophans, whose positions were varied in the primary structures, were located commonly at the critical amphipathic interface in the helical wheel projection. Helical conformations and the tryptophanyl environments of the 11 L 5K 5W peptides were confirmed and characterized by circular dichroism, fluorescence and nuclear magnetic resonance spectroscopy. All of the isomers exhibited a potent, broad-spectrum of antibacterial activity with just a slight variance in individual potency, whereas their hemolytic activities against human erythrocytes were significantly diversified. Interestingly, helical dispositions and fluorescence blue shifts of the peptides in aqueous trifluoroethanol solutions, rather than in detergent micelles, showed a marked linear correlation with their hemolytic potency. These results demonstrate that our de novo design strategy for amphipathic helical model peptides is effective for developing novel antimicrobial peptides and their hemolytic activities can be estimated in correlation with structural parameters.
Antimicrobial Peptides  [PDF]
Ali Adem Bahar,Dacheng Ren
Pharmaceuticals , 2013, DOI: 10.3390/ph6121543
Abstract: The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill “superbugs” emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial peptides (AMPs), a growing class of natural and synthetic peptides with a wide spectrum of targets including viruses, bacteria, fungi, and parasites. We summarize the major types of AMPs, their modes of action, and the common mechanisms of AMP resistance. In addition, we discuss the principles for designing effective AMPs and the potential of using AMPs to control biofilms (multicellular structures of bacteria embedded in extracellular matrixes) and persister cells (dormant phenotypic variants of bacterial cells that are highly tolerant to antibiotics).
Structural studies on the antimicrobial peptide Brevinin 1E by spectroscopic methods  [PDF]
Woo-Sung Son,Ji-Sun Kim,Hyung-Eun Kim,Sang-Ho Park,Bong-Jin Lee
Spectroscopy: An International Journal , 2003, DOI: 10.1155/2003/650369
Abstract: Skin extracts of frogs are a rich source of pharmacologically active peptides such as caeruleins, tachykinins, bradykinins, thyrotropin-releasing hormone, bombesin-like and opioid peptides. A large variety of antimicrobial peptides has been isolated from Rana species. These peptides, grouped in several families on the basis of differing length and distinct activity, were found to have one structural motif in common: an intramolecular disulfide bridge located at the C-terminal end, forming a seven-member ring, which was designated ‘Rana box’. Brevinin 1E is a 24-residue antimicrobial peptide isolated from the skin of a frog, Rana brevipoda. This peptide shows a broad range of antimicrobial activity against prokaryotic cells but shows very much hemolytic activity against human red blood cells. The solution structure of Brevinin 1E was studied by using CD (circular dichroism) and NMR (nuclear magnetic resonance) spectroscopy. CD investigation revealed that Brevinin 1E adopts random structure in aqueous solution but adopts mainly α-helical structure in TFE/water (6?: 4, v/v) solution. The three-dimensional structure of Brevinin 1E was determined in 60% TFE/water solution using homonuclear NMR spectroscopy. This peptide showed mainly an α-helical structure with amphipathic property. Its three-dimensional structure is similar to those of other peptides such as magainin, nigrocin and ranalexin. Therefore, Brevinin 1E can be classified into the family of antimicrobial peptides containing a single linear α-helix that interact with target microbial membrane, leading to cell death through disruption of membrane integrity.
The Potential of Antimicrobial Peptides as Biocides  [PDF]
Garry Laverty,Sean P. Gorman,Brendan F. Gilmore
International Journal of Molecular Sciences , 2011, DOI: 10.3390/ijms12106566
Abstract: Antimicrobial peptides constitute a diverse class of naturally occurring antimicrobial molecules which have activity against a wide range of pathogenic microorganisms. Antimicrobial peptides are exciting leads in the development of novel biocidal agents at a time when classical antibiotics are under intense pressure from emerging resistance, and the global industry in antibiotic research and development stagnates. This review will examine the potential of antimicrobial peptides, both natural and synthetic, as novel biocidal agents in the battle against multi-drug resistant pathogen infections.
Synchrotron radiation circular dichroism and conventional circular dichroism spectroscopy: A comparison  [PDF]
J. G. Lees,B. A. Wallace
Spectroscopy: An International Journal , 2002, DOI: 10.1155/2002/280646
Abstract: Conventional circular dichroism (cCD) spectroscopy is a valuable tool for secondary structure analyses of proteins. In recent years, it has been possible to use synchrotrons as light sources for CD, with the technique being known as Synchrotron Radiation Circular Dichroism (SRCD). In this study, the spectra of two proteins, the primarily helical myoglobin and the primarily beta?sheet concanavalin A, have been collected on both a cCD instrument and on the SRCD at the Daresbury synchrotron and their characteristics were compared. Over the wavelength regions where both instruments are capable of making measurements (from about 300 to 175 nm) the spectra are very similar, except at the low wavelength extreme of the cCD spectra. In this region, the spectra deviate somewhat, due to the limitations of the light source intensity in the conventional instrument. The SRCD spectra extend to much lower wavelengths (160 nm). This additional low wavelength vacuum ultraviolet (VUV) data contains a large amount of extra information, including, for the first time, a number of peaks consistent with previously predicted charge transfer transitions.
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