Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

Boman, Hans G.; Wade, David; Boman, I. A.; Wåhlin, B; Merrifield, R. B.

doi:10.1016/0014-5793(89)81505-4

Cited by 296 publications

(227 citation statements)

References 22 publications

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“…(18) to overcome the resistance of Gram-positive species such as Staph. aureus, and therefore they represent broaderspectrum antibiotics, which, in addition, do not lyse erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

All-D amino acid-containing channel-forming antibiotic peptides.

Wade

Boman

Wåhlin

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

654

492

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The D enantiomers of three naturally occurring antibiotics-cecropin A, magainin 2 amide, and melittin-were synthesized. In addition, the D enantiomers of two synthetic chimeric cecropin-melittin hybrid peptides were prepared. Each D isomer was shown by circular dichroism to be a mirror image of the corresponding L isomer in several solvent mixtures. In 20% hexafluoro-2-propanol the peptides contained 43-75% a-helix. The all-D peptides were resistant to enzymatic degradation. The peptides produced single-channel conductances in planar lipid bilayers, and the D and L enantiomers caused equivalent amounts of electrical conductivity. All of the peptides were potent antibacterial agents against representative Gram-negative and Gram-positive species. The D and L enantiomers of each peptide pair were equally active, within experimental error. Sheep erythrocytes were lysed by both D-and L-melittin but not by either isomer of cecropin A, magainin 2 amide, or the hybrids cecropin A-(1-13)-melittin-(1-13)-NH2 or cecropin A-(1-8)-melittin-(1-18)-NH2. The infectivity of the bloodstream form of the malaria parasite Plasmodium falciparum was also inhibited by the D and L hybrids. It is suggested that the mode of action of these peptides on the membranes of bacteria, erythrocytes, plasmodia, and artificial lipid bilayers may be similar and involves the formation of ion-channel pores spanning the membranes, but without specific interaction with chiral receptors or enzymes.The cecropins (1, 2) and several other antibiotic peptides of the animal kingdom, including defensins (3), magainins (4), and the bee venom toxin melittin (5), are thought to function through the formation of ion channels in lipid membranes. This idea has been based on recent studies of electrical conductivity in artificial lipid bilayers (3,(6)(7)(8), where activity is a function of the structure of the peptide and the composition of the membrane lipids. The bilayer lipids and cell membranes are chiral and contain many asymmetric centers. It has been generally assumed that the chirality of the membrane would require a specific chirality ofthe peptide for it to be active, in much the same way that peptide hormones are required to fit with the conformation of their natural receptors or for a substrate and enzyme to form a tight stereospecific complex. However, we have suggested that these peptide antibiotics can exert their effect without requiring a specific target receptor on the cell membrane (7, 9).The purpose of the present study was to test this assumption by the synthesis of the all-D enantiomers of several natural, all-L peptide antibiotics and some of their active analogs. These D stereoisomers would be expected to assume equivalent, but mirror image, conformations when placed in the same environment as the all-L peptides. If a close molecular contact with the chiral components of the cell membrane is required, the D enantiomers would be expected to be inactive. However, if the interaction of the peptide with the membrane is only between achiral...

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“…(18) to overcome the resistance of Gram-positive species such as Staph. aureus, and therefore they represent broaderspectrum antibiotics, which, in addition, do not lyse erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

All-D amino acid-containing channel-forming antibiotic peptides.

Wade

Boman

Wåhlin

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

654

492

View full text Add to dashboard Cite

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“…6). In fact, ceratotoxin A29 could be considered a non-haemolytic peptide, as its haemolytic concentration, eighttimes higher with respect to that of ceratotoxin A, is about 1 mM, whereas the haemolytic concentration of melittin is 4-8 pM (Boman et al, 1989) and that of bombinin H peptides from the skin of the amphibian Bornbina variegata is 16-17 pM (Mignogna et al, 1993). Nevertheless, ceratotoxins A and C, even at very high concentrations do not give a complete lysis as compared to melittin (Fig.…”

Section: A T T T C a G G A G C~g~g T T G C C A R G G T C G C C C A C mentioning

confidence: 99%

“…In fact, the tail of melittin was also suggested to be at least partly responsible for the haemolytic activity (Boman et al, 1989) but, in this case, the last six amino acids at the carboxy terminus of melittin are basic.…”

Section: A T T T C a G G A G C~g~g T T G C C A R G G T C G C C C A C mentioning

confidence: 99%

Molecular Characterization of Ceratotoxin C, a Novel Antibacterial Female‐Specific Peptide of the Ceratotoxin Family from the Medfly Ceratitis Capitata

Rosetto¹,

Manetti²,

Giordano³

et al. 1996

European Journal of Biochemistry

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Ceratotoxins A and B are antibacterial peptides produced by the sexually mature females of Cerutitis capitata. The gene expression is restricted to the female reproductive accessory glands, and is not affected by bacterial infection, but is enhanced by mating. We report here the purification and the amino acid sequence of ceratotoxin C, a novel member of the ceratotoxin family, the cloning of its cDNA and the analysis of its expression. Ceratotoxin C is coordinately expressed with the other members of the ceratotoxin family. Its antibacterial activity is directed against both Gram-negative and Gram-positive bacterial strains but it is lower than that of ceratotoxin A. We demonstrate in the genome of C. capitata the presence of at least three ceratotoxin genes which express, in the female accessory glands, a set of peptides presumably involved in the protection of the genital tract during fertilization.

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“…Taking CA(1-8)M(1-18) as lead, a subsequent approach was to further reduce the size of the hybrid CA-M peptides while retaining antimicrobial activity. This led to CA-(1-7)M(2-9), 9 a pentadecapeptide that preserves most of the activity of CA(1-8)M (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Interaction and Lipid-Induced Conformation of Two Cecropin−Melittin Hybrid Peptides Depend on Peptide and Membrane Composition

et al. 2005

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The interaction of two hybrid peptides of cecropin A and melittin [CA(1-8)M(1-18) and CA(1-7)M(2-9)] with liposomes was studied by differential scanning calorimetry (DSC), circular dichroism (CD), and quasi-elastic light scattering (QELS). The study was carried out with large unilamellar vesicles (LUVs) of three different lipid compositions: 1,2-dimyristoil-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoylsn-glycero-3-phospho-rac-(1-glycerol) (DMPG) and a binary mixture of DMPC/DMPG, in a wide range of peptide-to-lipid (P:L) molar ratios (0 to 1:7). DSC results indicate that, for both peptides, the interaction depends on membrane composition, with very different behavior for zwitterionic and anionic membranes. CD data show that, although the two peptides have different secondary structures in buffer (random coil for CA(1-7)M(2-9) and predominantly -sheet for CA(1-8)M(1-18)), they both adopt an R-helical structure in the presence of the membranes. Overall, results are compatible with a model involving a strong electrostatic surface interaction between the peptides and the negatively charged liposomes, which gives place to aggregation in the gel phase and precipitation after a threshold peptide concentration. In the case of zwitterionic membranes, a progressive surface coverage with peptide molecules destabilizes the membrane, eventually leading to membrane disruption. Moreover, delicate modulations in behavior were observed depending on the peptide.

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Antibacterial and antimalarial properties of peptides that are cecropin‐melittin hybrids

Cited by 296 publications

References 22 publications

All-D amino acid-containing channel-forming antibiotic peptides.

All-D amino acid-containing channel-forming antibiotic peptides.

Molecular Characterization of Ceratotoxin C, a Novel Antibacterial Female‐Specific Peptide of the Ceratotoxin Family from the Medfly Ceratitis Capitata

Interaction and Lipid-Induced Conformation of Two Cecropin−Melittin Hybrid Peptides Depend on Peptide and Membrane Composition

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