All-D amino acid-containing channel-forming antibiotic peptides.
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% alpha-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.
Wade
D
D
Rockefeller University, New York, NY 10021.
Boman
A
A
Wåhlin
B
B
Drain
C M
CM
Andreu
D
D
Boman
H G
HG
Merrifield
R B
RB
D000595:Amino Acid Sequence; D000596:Amino Acids; D023181:Antimicrobial Cationic Peptides; D001514:Bee Venoms / Q000138:chemical synthesis*; D002942:Circular Dichroism; D007301:Insect Hormones / Q000138:chemical synthesis*; D007473:Ion Channels / Q000502:physiology*; D007536:Isomerism; D007700:Kinetics; D054806:Magainins; D008555:Melitten / Q000138:chemical synthesis*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000378:metabolism; D029867:Xenopus Proteins
D000596:Amino Acids; D023181:Antimicrobial Cationic Peptides; D001514:Bee Venoms; D007301:Insect Hormones; D007473:Ion Channels; D054806:Magainins; D010455:Peptides; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus; D008555:Melitten; C031161:cecropin A; D014357:Trypsin