New strategies for novel antibiotics: peptides targeting bacterial cell membranes

Membranes are targets of host defence or antimicrobial peptides, effector molecules of innate immunity that evolved in nature to contend with invaders as an active system of defence. The different physicochemical properties of the lipids found in biological membranes allow antimicrobial peptides to discriminate between bacterial and mammalian cell membranes. Such cationic amphipathic peptides will interact predominantly with negatively charged lipids exposed on the outer leaflet of bacterial cell membranes. The molecular mechanism(s) of membrane rupture mutually depends on the nature of the peptide and membrane lipid composition. Biophysical studies demonstrated a complex behavior in terms of membrane perturbation, which can range from pore formation to micellization (carpet model). Peptides aligned parallel to the membrane surface can induce a quasi-interdigitated structure in the gel phase, while depending on the hydrophobic matching of the lipid bilayer core and the peptide membrane thinning or thickening can be observed in the fluid phase. As a consequence, besides of peptide-lipid pores, formation of peptide-enriched membrane domains and promotion of cubic structures can be observed, which adversely affect membrane integrity and function. A strategy using the membrane damaging properties of these peptides will form the basis for the development of such peptides as potential novel antibiotic drugs.