Permeabilization of the Mitochondrial Inner Membrane by Short Cecropin‐A–Melittin Hybrid Peptides

Abstract

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, 190–1941. 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(l–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 tenfold higher concentrations. Heparin potentiates the peptide effects at low concentrations, while at high concentration it becomes inhibitory. We propose that the cecropinmelittin analogs disrupt the mitochondrial membrane in a detergent‐like mode rather than by creating selective channels as had been previously suggested.

BMAP-28, an Antibiotic Peptide of Innate Immunity, Induces Cell Death through Opening of the Mitochondrial Permeability Transition Pore

“…1, plot B). No fluorescence variation was detectable when 3 M BMAP-28 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), the analogue peptide lacking the hydrophobic sequence (residues 19 to 27), was used ( Fig. 1, plot C) while the expected, dramatic decrease of FL2 fluorescent cells followed the treatment with the protonophore FCCP, used as a positive control (Fig.…”

“…A hallmark of most antimicrobial peptides is a membrane-permeabilizing activity, which has also been investigated in mitochondria, mostly used as model targets. Antibacterial peptides from insects (melittin and cecropins) and from mammals (magainins) as well as artificial short cecropin A-melittin hybrids have been shown to affect mitochondrial coupling and respiration (11,18). Finally, mastoparan, a peptide from the venom of Vespula laevis, has been shown to be a potent inducer of the PTP even in the absence of added Ca 2ϩ (32).…”

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

“…5 Cecropin A (CA) and melittin (M) provided the first examples of EAP sequence hybridization. [6][7][8] CA(1-8)M (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), one of the most successful examples of the hybridization concept, showed improved antimicrobial activity relative to parent cecropin A and greatly reduced the hemolytic properties of melittin. 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.…”

N-Terminal Fatty Acid Substitution Increases the Leishmanicidal Activity of CA(1-7)M(2-9), a Cecropin-Melittin Hybrid Peptide

“…Therapy based on the rational use of such peptides appears to be a feasible alternative, and successful preliminary results have been reported for natural peptides such as dermaseptins (19,23), SPYY (47), cecropin A (1), and gomesin (42), all of which have been shown to be active against different forms of the parasite. In our own work, we have expanded the repertoire of peptides with activity against Leishmania with cecropin-melittin hybrids such as CA (1)(2)(3)(4)(5)(6)(7)(8)M (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and CA(1-7)M(2-9), both of which are active in the micromolar range (15).…”