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At least 19 recordsLinked to original sources
PubMed1990

Phosphorylation of magainin-2 by protein kinase C and inhibition of protein kinase C isozymes by a synthetic analogue of magainin-2-amide.

Magainins are a family of antimicrobial peptides present in the skin extracts of Xenopus laevis. Both magainin-1 and -2 do not have any significant effect on the activity of protein kinase C (PKC). Magainin-2 was found to be readily phosphorylated by PKC to 0.5 mol 32P/mol of peptide. Neither magainin-1, which has a sequence of S8AGK and not S8AKK as in the case of magainin-2, nor the magainin-2 analogue with substitution of Ala for Ser8 was phosphorylated by the kinase, suggesting that Ser8 is the phosphorylation site of magainin-2. One synthetic analogue of magainin, designated magainin B, which has a greater tendency for alpha-helix formation in non-aqueous environment than the parent peptide resulting from substitution of Ser8, Gly13, and Gly18 with Ala in magainin-2-amide, is a potent inhibitor of PKC. This peptide inhibits all three PKC isozymes with IC50 less than 20 microM. Magainin B also inhibits the binding of [3H]phorbol 12,13-dibutyrate to the kinase. These results suggest that magainin-2 may be modified by PKC through phosphorylation and that certain synthetic analogues of magainins may be used as inhibitors of PKC.

Amino Acid Sequence↗
PubMed1995

Functional synergism of the magainins PGLa and magainin-2 in Escherichia coli, tumor cells and liposomes.

Xenopus laevis skin secretion contains a mixture of magainins, which are small positively charged oligopeptides with antimicrobial activity. In this study, we show that two of these peptides, i.e. magainin-2 and PGLa, are much more active in biological functions when added together than when added alone. This synergy applies for the antimicrobial activity of these peptides, and for the toxic effects on tumor cells. We show that this peptide combination is also synergistic when permeabilizing protein-free liposomes for glucose, when dissipating the membrane potential in cytochrome oxidase liposomes and Escherichia coli, and, reversibly, when stimulating respiration in the liposomes. The occurrence of synergy in these diverse systems (complex and simple) suggests that the biological synergy results from synergy in the primary activity of the magainin peptides, namely the permeabilization of free-energy transducing membranes, possibly by forming a multimeric transmembrane pore of mixed peptide composition. The antimicrobial activity of X. laevis skin secretions may be greatly enhanced by the application of this binary weapon.

Amino Acid Sequence↗
PubMedDate not supplied

The Magainins: sequence factors relevant to increased antimicrobial activity and decreased hemolytic activity.

The Magainins, two antimicrobial peptides found in the skin of the frog Xenopus laevis, and 50 Magainin analogs were synthesized by the method of simultaneous multiple peptide synthesis (SMPS). This series of peptides was prepared in order to examine the effects of omitting individual amino acids on antimicrobial activity. The series consisted of 22 Magainin 1 omission analogs having a C-terminal carboxyl (M1-C) and 23 Magainin 2 omission analogs having a C-terminal amide (M2-A), as well as both the C-terminal amide and carboxyl forms of Magainin 1 and Magainin 2. These peptides were tested against E. coli (Gram negative), S. epidermis (Gram positive) and C. albicans (yeast). Amino acid omissions in the N-terminal region (residues 1-14) resulted in the complete loss of antimicrobial activity in both Magainin series. These analogs also had very low hemolytic activity against human erythrocytes. However, analogs with omissions in the C-terminal region, especially residues alanine-15, glycine-18 or glutamic acid-19, while having equal or increased antimicrobial activity relative to the original Magainin 1 or Magainin 2 forms, had variable hemolytic action. Thus, both Magainin 1 and Magainin 2 with the glutamic acid 19 omission had equal activity against E. coli and increased activity against S. epidermis, while having lower hemolytic activity than the original sequences. The amide form of Magainin 2 with glycine 18 omitted had equal antimicrobial activity, but significantly increased hemolytic activity. The C-terminal carboxyl form of Magainin 1, however, showed equal antimicrobial activity, but substantially decreased hemolytic action.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2006

Antitumor activity of the antimicrobial peptide magainin II against bladder cancer cell lines.

OBJECTIVE: Magainin II belongs to a family of antimicrobial peptides and has been shown to exhibit antibiotic activity in a wide range of organisms. Recent studies have also reported a significant antitumor effect of magainin II against various cancer cell lines and tumor mice models. In this study, we evaluated the cytotoxic and antiproliferative potency of magainin II in bladder tumor cells and normal fibroblasts. METHODS: The antiproliferative and cytotoxic effect of magainin II was quantified by colorimetric WST-1-, bromodeoxyuridine (BrdU)-, and lactic dehydrogenase (LDH) assays in three bladder cancer cell lines (RT4, 647V, and 486P) and in the murine fibroblast cell line 3T3 as well as in a primary culture from human fibroblasts. The median inhibitory concentration (IC50) values were determined for each assay, representing the concentration at which cell viability was reduced by 50%. Scanning electron microscopy (SEM) was used to visualize the morphologic effects of magainin II on bladder tumor cells and fibroblasts. RESULTS: Magainin II inhibited cell proliferation of bladder cancer cells in a dose-dependent manner. The average IC50 of magainin II against all bladder cancer cell lines was 198.1 microM (range, 52.4-484.03 microM) for the WST-1 assay and 75.2 microM (range, 31.0-135.3 microM) for the BrdU assay. The normal murine and human fibroblast cell lines were not affected by magainin II and their IC50 could not be determined at the concentrations of magainin II tested. LDH release was increased in all bladder tumor cell lines in the presence of magainin II, whereas normal fibroblasts showed no cell lysis. SEM demonstrated lethal membrane perforation by peptide pore formation in bladder cancer cells, but not in fibroblasts. CONCLUSION: Magainin II peptide exerts cytotoxic and antiproliferative efficacy by pore formation in bladder cancer cells but has no effect on normal murine or human fibroblasts. Magainin II may offer a novel therapeutic strategy in the treatment of bladder cancer with potentially low cytotoxic effects on normal cells.

Antimicrobial Cationic Peptides↗
PubMed1997

The tendency of magainin to associate upon binding to phospholipid bilayers.

Fluorescence energy transfer (FET) from [Trp16]-magainin-2-amide (Trp-Mag) and [D-Ala15,D-Trp16]magainin-2-amide (DD-Trp-Mag) to N(alpha)-dansyl-magainin-2-amide (DNS-Mag) was used to study the association of magainin 2 analogs bound to phosphatidylglycerol vesicles. As shown by circular dichroism and fluorescence spectroscopy, the all-L-analogs exist in a helical conformation and are completely bound to the lipid membrane. The observed FET between Trp-Mag and DNS-Mag is rather small and increases with the DNS-Mag surface concentration. The experimentally determined transfer efficiency is lower than predicted for monomeric magainin analogs randomly distributed exclusively at the outer leaflet of lipid vesicles. These observations can be explained by two different models of spatial distribution for the monomeric magainin analogs. The first model takes into account translocation of magainin which might result in a uniform distribution of magainin at the inner and outer vesicle leaflets. The second model assumes that at least one shell of lipids exists between two magainin molecules, thus reducing the probability of direct contact. Both models explain the measured FET without any contribution of stable associates of magainin analogs. Furthermore, for Trp-Mag and DD-Trp-Mag, an identical energy transfer efficiency was observed, although the nonhelical double-D substituted analog should have a significantly reduced association tendency resulting in decreased FET. Our conclusion that the observed FET is not the result of magainin association is confirmed by the equivalence of the measured energy transfer efficiencies.

Anti-Infective Agents↗
PubMed1994

Expression of magainin antimicrobial peptide genes in the developing granular glands of Xenopus skin and induction by thyroid hormone.

The granular gland of amphibian skin is an epithelial derivative that first appears during metamorphosis. The granular glands of Xenopus laevis are an abundant source of magainins, a family of peptides with antimicrobial activity in vitro. We demonstrate the developmental expression and thyroid hormone induction of magainin and PGLa (peptide with aminoterminal glycine and carboxyterminal leucinamide), the two most abundant members of the magainin peptide family. Magainin and PGLa mRNA levels increase dramatically over the 2-day period between stage 58 and stage 60 and remain high during the remainder of metamorphosis. We used in situ hybridization to localize magainin and PGLa mRNAs to the developing granular gland. Magainin and PGLa peptides are also first detected during metamorphosis, as demonstrated by extraction of active peptides from stage 60 tadpoles and immunogold histochemical localization of magainin and PGLa to the granules of the skin granular gland. We demonstrate the premature induction of magainin and PGLa expression upon administration of exogenous thyroid hormone to stage 54 tadpoles. Further investigation of the developmental expression and induction of the magainin peptides will provide insight into their possible biological functions during Xenopus metamorphosis.

Animals↗
PubMed2005

Single giant unilamellar vesicle method reveals effect of antimicrobial peptide magainin 2 on membrane permeability.

It is thought that magainin 2, an antimicrobial peptide, acts by binding to lipid membranes. Recent studies using a suspension of large unilamellar vesicles (LUVs) indicate that magainin 2 causes gradual leakage from LUVs containing negatively charged lipids. However, the details of the characteristics of the membrane permeability and the mechanism of pore formation remain unclear. In this report, we investigated the interaction of magainin 2 with single giant unilamellar vesicles (GUVs) composed of a dioleoylphosphatidylcholine and dioleoylphosphatidylglycerol mixture (50% DOPG/50% DOPC GUVs) containing the fluorescent dye, calcein, by phase contrast, fluorescence microscopy using the single GUV method. Low concentrations (3-10 microM) of magainin 2 caused the rapid leakage of calcein from single GUVs but did not disrupt the liposomes or change the membrane structure, showing directly that magainin 2 forms membrane pores through which calcein leaked. The rapid leakage of calcein from a GUV started stochastically, and once it began, the complete leakage occurred rapidly (6-60 s). The fraction of completely leaked GUV, P(L), increased with time and also with an increase in magainin 2 concentration. Shape changes in these GUVs occurred prior to the pore formation and also at lower concentrations of magainin 2, which could not induce the pore formation. Their analysis indicates that binding of magainin 2 to the external monolayer of the GUV increases its membrane area, thereby raising its surface pressure. The addition of lysophosphatidylcholine into the external monolayer of GUVs increased P(L). On the basis of these results, we propose the two-state transition model for the pore formation.

Antimicrobial Cationic Peptides↗
PubMed1997

Modulation of magainin 2-lipid bilayer interactions by peptide charge.

Magainin 2, an antimicrobial peptide from Xenopus skin, assumes an amphiphilic helix when bound to acidic phospholipids, forming a pore composed of a dynamic, peptide-lipid supramolecular complex [Matsuzaki et al. (1996) Biochemistry 35, 11361-11368]. Upon the disintegration of the pore, a fraction of the peptide molecules stochastically translocates across the bilayer (Matsuzaki, et al., 1995). In order to investigate the effects of peptide charge on the magainin 2-lipid bilayer interactions, we synthesized four magainin 2 analogs with different charges (0-6+). MG0: K10E, K11E, F12W-magainin 2. MG2+: K10E, F12W-magainin 2. MG4+: F12W-magainin 2. MG6+: F12W, E19Q-magainin 2 amide. An increase in charge resulted in a stronger binding of the peptide to the negatively charged membranes, suggesting that electrostatic attractions play a crucial role in the binding process. The helical stability in a trifluoroethanol/buffer mixture was decreased with increasing positive charge because of electrostatic repulsions between the closely spaced positive side chains, whereas the helicity in the lipid bilayer was much higher and appeared to be independent of the peptide charge. However, enhanced repulsions between the highly positively charged helices destabilized the pore. Therefore, the efficiency of the most basic peptide (MG6+) to translocate across the bilayer was the greatest by virtue of the short life span of its pore and the very tight membrane binding. The charge distribution of wild-type magainin 2 was found to be so designed as to exhibit the maximal lytic activity by simultaneously achieving a strong binding and a moderate pore stability.

Amino Acid Sequence↗
PubMed1991

Beta-lactam antibiotics potentiate magainin 2 antimicrobial activity in vitro and in vivo.

The ability of magainin 2 to augment antibiotic therapy was examined. Susceptibility to magainin 2 was determined on Escherichia coli incubated in the presence and absence of sublethal concentrations of antibiotics both in vitro and in vivo. Experiments in buffer and normal human serum revealed that E. coli exposed to sublethal amounts of cefepime, a beta-lactam antibiotic, was significantly more susceptible to the antimicrobial activity of magainin 2. Bacteria incubated with subinhibitory concentrations of other beta-lactam type antibiotics, but not amikacin (an aminoglycoside) or ciprofloxacin (a quinolone), were also more susceptible to magainin 2 in normal human serum. Bacteria were less susceptible to magainin 2 when they were examined in heat-inactivated serum. Complement was shown to be required for magainin 2 activity in serum by using C8-deficient sera. The combination of magainin 2 and cefepime was shown to be more antimicrobial in normal human serum for a variety of bacterial strains. Magainin 2 was completely inactive as a therapeutic agent when it was administered alone (2 mg per mouse) but significantly increased the survival of mice when it was administered with a low level of cefepime.

Animals↗
PubMed2005

In vitro biological activities of magainin alone or in combination with nisin.

Antimicrobial peptides have received increasing attention not only as potential candidates to their administration as antimicrobial agents, but also as potential drugs applied in cancer therapy. Here, we have examined the action of both nisin and magainin on human promyelocytic leukemia HL-60 cells. Cells were cultured in presence of either nisin or magainin 1 as well as in combination with both nisin and magainin 1. Results have revealed that magainin, but not nisin, produces a loss of cell viability in HL-60 cells, and a minor increase of hemolysis, whereas it is not responsible for cell membrane disruption and lactate dehydrogenase (LDH) leakage. In addition, magainin is involved in a significant generation of reactive oxygen species (ROS), as well as in an augment of caspase-3 activity. Magainin-induced apoptosis was verified by DNA fragmentation and annexin V-FITC/propidium iodide (PI) staining of the cells. Promotion of cell death by magainin occurs via cytochrome c release accompanied by a substantial increase of proteasome activity. These results underline the importance of magainin as a drug capable of exerting an in vitro antitumoral activity by triggering apoptosis.

Anti-Bacterial Agents↗
PubMed2002

Magainin 2 channel formation in planar lipid membranes: the role of lipid polar groups and ergosterol.

Magainin 2, a polycationic peptide, displays bactericidal and tumoricidal activity, presumably interacting with negatively charged phospholipids in the membrane hosts. In this work, we investigate the role played by the lipid head-group in the interactions and self-association of magainin 2 during pore formation in lipid bilayers. Two methods are used: single-channel and macroscopic incorporation into planar lipid membranes. Single-channel incorporation showed that magainin 2 did not interact with zwitterionic membranes, while the addition of negatively charged dioleoylphosphatidylglycerol to the membrane leads to channel formation. On the other hand, magainin 2 did not form channels in membranes made up of dioleoylphosphatidylserine (DOPS), although the addition of ergosterol to DOPS membranes leads to channel formation. This finding could indicate that ergosterol may be a possible target of magainin 2 in fungal membranes. Further support for this hypothesis comes from experiments in which the addition of ergosterol to palmitoyloleoylphosphatidylcholine membranes induced channel formation. Besides the role of negatively charged membranes, this study has shown that magainin 2 also forms channels in membranes lacking heads, such as monoolein and oxidized cholesterol, indicating an interaction of magainin 2 with acyl chains and cholesterol, respectively. This finding provides further evidence that peptide binding and assembly in lipid membranes is a complex process driven by electrostatic and/or hydrophobic interactions, depending on the structure of the peptide and the membrane composition.

Antimicrobial Cationic Peptides↗
PubMed1993

Electric potentiation, cooperativity, and synergism of magainin peptides in protein-free liposomes.

Magainins, positively charged peptides present in the skin of Xenopus laevis, are known to permeabilize free-energy transducing membranes. Structural studies in otherwise protein-free model systems show alpha-helical magainins parallel to the membrane water interface. However, functional studies in biological membranes suggest that magainins operate as oligomeric complexes. Here we investigate whether magainins function as oligomers in protein-free liposomes also. We report that they do exhibit strong positive heterocooperativity. The magainins, magainin 2 and PGLa, act synergistically. Both activity and cooperativity are enhanced by net negative charge of the liposomal membranes. A transmembrane electric potential, negative inside, enhanced the activity of the peptides. We propose a model in which (i) binding to the surface of the membrane, mainly guided by electrostatic interactions, occurs and (ii) the bound form is in equilibrium with an n-meric complex of magainins spanning the membrane.

Amino Acid Sequence↗
PubMed2001

Embryotoxicity of magainin-2-amide and its enhancement by cyclodextrin, albumin, hydrogen peroxide and acidification.

BACKGROUND: The channel-forming antimicrobial peptide, magainin-2-amide, interacts preferentially with negatively charged, non cholesterol-containing membranes, including those of sperm, oocytes and cells of pre-implantation embryos. Cyclodextrin and albumin remove membrane cholesterol and together with hydrogen peroxide (H2O2) are potential enhancers of embryotoxicity. METHODS: Two-cell murine embryos were cultured in vitro with magainin-2-amide at a high effective concentration (250 microg/ml) and at subthreshold concentrations (166 and 200 microg/ml). Embryos treated with sub-threshold concentrations of magainin were additionally treated with cyclodextrin, bovine serum albumin or H2O2 or were cultured under acidified conditions. Cell viability was verified with propidium iodide and fluorescein diacetate. RESULTS: The embryotoxic effect of magainin and H2O2 was dose- and time-dependent. Cyclodextrin, H2O2, acidification of the medium, and to a lesser extent albumin, enhanced the embryotoxicity of magainin at sub-threshold concentrations. CONCLUSION: Magainin on its own is highly embryotoxic. Its embryotoxicity is enhanced by cyclodextrin, albumin, H2O2 and acidification. Thus, magainin which has antibacterial, antifungal and antiprotozoal activity may also have a potential role as a contraceptive agent. The harmful effects of various concentrations of the exogenous H2O2 on 2-cell stage mouse embryos are reported here, to the best of our knowledge, for the first time.

Animals↗
PubMed2002

Single-dose intraperitoneal magainins improve survival in a gram-negative-pathogen septic shock rat model.

The therapeutic efficacies of three polycationic peptides selected among the class of the magainins (magainin I, magainin II, and magainin II amide), alone and combined with piperacillin, were investigated in a rat model of septic shock. Rats were given an intraperitoneal injection of 2 x 10(10) CFU of Escherichia coli and randomized to receive intraperitoneally isotonic sodium chloride solution, 60 mg of piperacillin per kg of body weight, and 1 mg of each magainin per kg alone and combined with 60 mg of piperacillin per kg. The main outcome measures were bacterial growth in abdominal exudate and plasma, endotoxin and tumor necrosis factor alpha (TNF-alpha) concentrations in plasma, and lethality. Treatments with the magainins achieved significant reductions of bacterial growth and plasma endotoxin and TNF-alpha concentrations. In general, treatments with the combinations of magainins and piperacillin demonstrated the highest efficacies.

Animals↗
PubMed2004

Preclinical evaluation of magainin-A as a contraceptive antimicrobial agent.

OBJECTIVE: To evaluate the safety and contraceptive efficacy of magainin-A in monkeys. DESIGN: Controlled laboratory study. SETTING: Department of Immunology, National Institute for Research in Reproductive Health, Parel, Mumbai, India. ANIMAL(S): Male and female bonnet monkeys (Macaca radiata). INTERVENTION(S): Animals were treated intravaginally with 1 mg of magainin-A before attempted conception, as well as daily for 14 days to assess local and systemic toxicity. MAIN OUTCOME MEASURE(S): Suitability of magainin-A for the control of pregnancy and sexually transmitted infections. RESULT(S): Complete sperm immobilization was observed within 20 seconds after the exposure to magainin-A (800-1,000 microg) in vitro. Intravaginal administration of 1 mg of magainin-A blocked conception in monkeys. When magainin-A was administered intravaginally for 14 consecutive days, no treatment-related abnormalities were observed in menstrual cycle length, vaginal epithelial cell morphology, and hematologic/serum biochemical profiles. The peptide inhibited the growth of sexually transmitted infection-causing pathogens but not HIV-1 and HIV-2. CONCLUSION(S): Magainin-A can be used as an effective and safe intravaginal contraceptive compound with additional protection against sexually transmitted infection-causing pathogens.

Animals↗
PubMed2001

Effect of magainin, class L, and class A amphipathic peptides on fatty acid spin labels in lipid bilayers.

Magainins and other antimicrobial peptides increase ion flux across the membrane. They may do this by forming some type of pore or by perturbing lipid organization due to peptide lying on the bilayer surface. In order to determine if magainins perturb the lipid sufficiently to permeabilize the bilayer, their effect on the motion of fatty acid and lipid spin labels in phosphatidylcholine/phosphatidylglycerol (PC/PG) lipid vesicles was determined. Their effect was compared to two synthetic peptides, 18L and Ac-18A-NH(2), designed to mimic the naturally occurring classes of lytic (class L) and apolipoprotein (class A) amphipathic helices, respectively. We show that although magainins and 18L both had significant effects on lipid chain order, much greater than Ac-18A-NH(2), there was no correlation between these effects and the relative ability of these three peptide classes to permeabilize PC/PG vesicles in the order magainins=Ac-18A-NH(2) >> 18L. This suggests that the perturbing effects of magainins on lipid chain order at permeabilizing concentrations are not directly responsible for the increased leakage of vesicle contents. The greater ability of the magainins to permeabilize PC/PG vesicles relative to 18L is thus more likely due to formation of some type of pore by magainins. The greater ability of Ac-18A-NH(2) relative to 18L to permeabilize PC/PG vesicles despite its lack of disordering effect must be due to its ability to cause membrane fragmentation. Effects of these peptides on other lipids indicated that the mechanism by which they permeabilize lipid bilayers depends both on the peptide and on the lipid composition of the vesicles.

Amino Acid Sequence↗
PubMed1994

Potential therapeutic applications of magainins and other antimicrobial agents of animal origin.

Magainins are a family of linear, amphipathic, cationic antimicrobial peptides, 21 to 27 residues in length, found in the skin of Xenopus laevis. They kill microbial targets through disruption of membrane permeability. They exhibit selectivity, on the basis of their affinity for membranes which contain accessible acidic phospholipids, a property characterizing the cytoplasmic membranes of many species of bacteria. Magainins are broad-spectrum antimicrobial agents exhibiting cidal activity against Gram-negative and Gram-positive bacteria, fungi and protozoa. In addition these peptides lyse many types of murine and human cancer cells at concentrations 5-10-fold lower than normal human cells. Because of their selectivity, broad spectrum, low degree of bacterial resistance and ease of chemical synthesis, magainins are being developed as human therapeutic agents. The most advanced candidate is MSI-78, a 22-residue magainin analogue. This peptide is currently in human Phase IIb/III clinical trials in studies intended to evaluate its efficacy as a topical agent for the treatment of impetigo. Preclinical studies have demonstrated that analogues of magainin exhibit activity in vivo against malignant melanoma and ovarian cancer cells in mouse models. Intravenous administration of several magainin analogues has been shown to treat effectively systemic Escherichia coli infections in the mouse.

Amino Acid Sequence↗
PubMed1992

Magainin 2, a natural antibiotic from frog skin, forms ion channels in lipid bilayer membranes.

We have examined the ion channel forming properties of magainin 2 by incorporating the peptide into artificial lipid bilayers held under voltage clamp. Magainin 2 increased lipid bilayer conductance in a concentration dependent manner with a Hill coefficient of 1.7. The magainin 2 conductance was selective for monovalent cations over anions with a ratio of 5:1 and had both voltage-sensitive and -insensitive components. Two structurally related but antibiotically less potent analogues, magainin 1 and Z-12, also increased lipid bilayer conductance with a similar ion selectivity but these peptides were less potent than magainin 2. We propose that the weak cation selectivity of the magainin channels can be accounted for by the inclusion of negatively charged lipids in the channel complex and suggest two possible structures for such a channel. The ionophoric properties of these peptides are likely to be proximal to their antibiotic activities.

Animals↗