Permeabilization of the mitochondrial inner membrane by short cecropin-A-melittin hybrid peptides.
A number of cecropin-A-melittin hybrid peptides have previously been shown to be potent antibacterial agents [Andreu, D., Ubach, J., Boman, A., Wahlin, B., Wade, D., Merrifield, R. B. & Boman, H. G. (1992) FEBS Lett. 296, 190-194]. In the present report we analyze their action on biological systems using rat liver mitochondria as a test system. We demonstrate that the longest peptide, cecropin-A-(1-8)-melittin(1-18) permeabilizes the mitochondrial inner membrane allowing the movement of both charged and non-charged solutes. Concentrations used have already been shown to be bactericidal. This effect is also demonstrated under respiring conditions where succinate oxidation is uncoupled. Shorter analogs also permeabilize mitochondria although at ten-fold higher concentrations. Heparin potentiates the peptide effects at low concentrations, while at high concentration it becomes inhibitory. We propose that the cecropin-melittin analogs disrupt the mitochondrial membrane in a detergent-like mode rather than by creating selective channels as had been previously suggested.
Díaz-Achirica
P
P
Centro de Investigaciones Biológicas, C.S.I.C., Madrid, Spain.
Prieto
S
S
Ubach
J
J
Andreu
D
D
Rial
E
E
Rivas
L
L
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D003902:Detergents; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D008555:Melitten / Q000378:metabolism / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D010101:Oxygen Consumption; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D003902:Detergents; D011993:Recombinant Fusion Proteins; D008555:Melitten; C031161:cecropin A; D006493:Heparin