Antibacterial peptides (AMPs) are naturally occurring small protein fragments that can effectively kill microorganisms. They are capable of binding to the negatively charged membranes of bacteria through electrostatic and hydrophobic interactions, thereby disrupting their structure and killing them. The AMPs are generally cationic in nature and have a strong affinity for the negatively charged lipids of bacterial membrane such as cardiolipin, phosphatidylglycerol and sphingomyelin. However, the AMPs do not have significant interaction with the zwitterionic phospholipids found in mammalian cell membranes which are composed of phosphatidylcholine, phosphatidylethanolamine, and huge concentration of cholesterol. This reduces their cytotoxicity towards eukaryotic cells.
Depending on their capability to form pores in the bacterial membrane, AMPs can be broadly classified into two categories of MOA: Membrane targeting and non-membrane targeting. The former group includes peptides which can be further categorized into four models including barrel-stave, toroidal pore wormhole and carpet model while the latter comprises those AMPs which are not capable of forming membrane perforation .
The structural characteristics of AMPs such as amino acid sequence, net charge, secondary structure, amphipathicity and hydrophobicity are essential for their effective interaction with bacterial cell membranes. Furthermore, post-translational modification of AMPs such as amidation or C-terminal amide capping can enhance the membrane binding activity of these molecules without increasing their lytic potential.
Lipidation of AMPs also increases their resistance to proteases and peptidases, decreases their cytotoxicity, and stabilizes the secondary structures of the AMPs. Hydrophobic terminal labeling such as acetylation or amide capping at the N-terminus is another common way of improving the antimicrobial properties of AMPs.