Interaction of cationic peptides with bacterial membranes.

A common feature of cationic peptides is that their site of action is at the membrane due to channel formation, and that they tend to possess strong selectivity towards their target membrane. For example, although moth cecropin and bee melittin are members of the same family of peptides that adopt amphipathic a-helical structures, the cecropins are strongly antibacterial and demonstrate minimal eukaryotic selectivity (i.e., toxicity), whereas melittin is a weak antibacterial compound but a potent toxin. Whereas the basis for selectivity is not completely understood, it has been shown to be due to the size of the transmembrane electrical potential gradient (up to -140 mV in bacterial cytoplasmic membranes compared with about -20 mV or less in eukaryotic membranes) and the lipid composition (bacterial membranes contain a large number of anionic lipids such as phosphatidyl glycerol and cardiolipin and lack cholesterol in their membranes). Gram-negative bacteria have an additional, outer membrane, and our data suggests that a further level of selectivity is expressed there in that there are Gram-positive bacteria-selective peptides that interact poorly with the outer membrane but (presumably) well with cytoplasmic membranes, whereas we have identified peptides that interact with the outer membrane, but are not bactericidal and thus do not interact with cytoplasmic membranes. Although specific details may vary depending on the peptide, enough data exist to present a general model for the mechanism of action of cationic peptides against Grara-negative bacteria. This process is described below, and can be summarized as a sequence of events involving interaction with lipopolysac-