Mode of action of membrane active antimicrobial peptides

Abstract

Water-membrane soluble protein and peptide toxins are used in the defense and offense systems of all organisms, including plants and humans. A major group includes antimicrobial peptides, which serve as a nonspecific defense system that complements the highly specific cell-mediated immune response. The increasing resistance of bacteria to conventional antibiotics stimulated the isolation and characterization of many antimicrobial peptides for potential use as new target antibiotics. The finding of thousands of antimicrobial peptides with variable lengths and sequences, all of which are active at similar concentrations, suggests a general mechanism for killing bacteria rather than a specific mechanism that requires preferred active structures. Such a mechanism is in agreement with the "carpet model" that does not require any specific structure or sequence. It seems that when there is an appropriate balance between hydrophobicity and a net positive charge the peptides are active on bacteria. However, selective activity depends also on other parameters, such as the volume of the molecule, its structure, and its oligomeric state in solution and membranes. Further, although many studies support that bacterial membrane damage is a lethal event for bacteria, other studies point to a multihit mechanism in which the peptide binds to several targets in the cytoplasmic region of the bacteria.

Membrane interactions of designed cationic antimicrobial peptides: The two thresholds

“…4L 8,11,13,16 , displayed the highest hemolytic profile (up to 50%), while magainin II amide showed almost complete hemolysis at all concentrations tested. Isomers with the same number of Ala-to-Leu mutations showed similar but not identical activities; for example, 6K-F17-2L 11,13 showed the lowest hemolytic activity among double-substituted isomers.…”

“…CAPs likely attach in an asymmetrical manner from the outer leaflet of the biological membrane, and penetrate it, physically disrupting the bacterial cellular bilayer, leading to lysis and eventually cell death. 11 The activity of CAPs on each particular cell membrane is differentiated by variations in their lipid composition. 3 Thus, for mammalian cells, the primary plasma membrane features are an essentially neutral (zwitterionic) outer leaflet, the presence of cholesterol (up to 25 mol%), and predominance of phosphatidylcholine lipids.…”

“…Several thousand additional antimicrobial peptides have been designed de novo and produced synthetically. 11 The increasing prevalence of antibiotic resistance necessitates the development of new and efficient ways to combat bacterial infection. CAPs are potential candidates and offer a viable alternative to conventional antibiotics because of their broad activity spectrum (antibacterial, antiviral and antifungal), rapid onset of killing, and potentially low levels of induced resistance.…”

“…14 Biophysical studies have demonstrated that there are some general nonreceptor-mediated mechanisms responsible for peptide antimicrobial activity, which appear to involve permeabilization of phospholipid bilayer membranes via ''barrel-stave,'' ''toroidal pore,'' or ''carpet detergent-like'' arrangements. 3,8,11,15 Since the majority of antimicrobial peptides are positively charged at physiological pH, while outer leaflets of mammalian and bacterial plasma membranes are totally neutral and anionic, respectively, the mechanisms of their antimicrobial and hemolytic activities might differ in detail.…”

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…Besides phospholipid-binding antibodies, innate defense molecules can also target the altered cell surface phospholipid profile of tumor cells. Cationic antimicrobial peptides (CAPs) are a class of small (o5 kDa) positively charged innate defense molecules that act primarily to destabilize or penetrate the membrane of microbial cells, in some cases via interactions with specific phospholipids 47,48 (functioning as phospholipid detectors). Interestingly, CAPs originated from different species including plants, insects, amphibians, mammals have been shown to possess antiproliferative activity towards mammalian tumor cells both in vitro and in vivo (reviewed in detail by Riedl et al 49 ).…”