Correlation between anti-bacterial activity and pore sizes of two classes of voltage-dependent channel-forming peptides.
Anti-bacterial activities were compared for two series of voltage-dependent pore-formers: (i) alamethicin (Alm) and its synthetic analogs (Alm-dUL) where alpha-amino-isobutyric acid residues (Aibs) were replaced by leucines and selected key residues substituted and (ii) homologous voltage sensors of the electric eel sodium channel (repeats S4L45 (III) and S4L45 (IV)). Spiroplasma melliferum, a bacterium related to the mycoplasmas, was used as a target cell. The data show that with respect to growth inhibition, cell deformation and plasma membrane depolarization, the highest efficient peptide remained natural Alm although the minimal inhibitory concentrations of its Leu analogs were within the same range as the parent molecule, except for Alm-dUL P14A. Thus, as for the pore-forming activity observed in artificial membranes and for the toxicity towards mammalian cells, proline-14 proved to be a critical residue for the anti-bacterial activity of alamethicin. Regarding the sodium voltage sensors, their anti-bacterial efficiency was at least 10 times lower although they promoted spiroplasma cell agglutination. The anti-bacterial activities of the peptides were correlated with their pore-forming properties, especially with the apparent and mean number of monomers per conducting aggregate (<N>) when both peptide families were considered and, secondly, with mean open times (tau(o)) within each family. This suggests that although they may form 'raft-like' structures, the mechanism underlying anti-bacterial activity of Alm and its active analogs, as well as the S4L45 voltage sensors with the S. melliferum plasma membrane, is predominantly through pore-formation according to the 'barrel-stave' mechanism.
Béven
L
L
Université de Rennes 1, UPRES-A CNRS 6026, GDR CNRS 790, Campus de Beaulieu, 35042, Rennes Cedex, France.
Helluin
O
O
Molle
G
G
Duclohier
H
H
Wróblewski
H
H
D000408:Alamethicin / Q000737:chemistry; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004553:Electric Conductivity; D007473:Ion Channels / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D018272:Porins / Q000737:chemistry* / Q000494:pharmacology; D013149:Spiroplasma / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development; D050994:Voltage-Dependent Anion Channels
D000900:Anti-Bacterial Agents; D007473:Ion Channels; D018272:Porins; D050994:Voltage-Dependent Anion Channels; D000408:Alamethicin