Mechanisms of action of antibacterial peptides. The bacterial membrane is represented as a yellow lipid bilayer with the peptides shown as cylinders, where the hydrophilic regions are colored red and the hydrophobic regions are blue. Cell wall-associated peptidoglycan molecules are depicted as purple cylinders. Models to explain mechanisms of membrane permeabilization are indicated (A to D). In the “aggregate” model (A), peptides reorient to span the membrane as an aggregate with micelle-like complexes of peptides and lipids, but without adopting any particular orientation. The “toroidal pore” model (B) proposes that peptides insert perpendicular to the plane of the bilayer, with the hydrophilic regions of the peptides associating with the phospholipid head groups while the hydrophobic regions associate with the lipid core. In this process, the membrane also curves inward such that the bilayer also lines the pore. In the “barrel-stave” model (C), the peptides insert in a perpendicular orientation to the plane of the bilayer, forming the “staves” in a “barrel”-shaped cluster, with the hydrophilic regions of the peptides facing the lumen of the pore and the hydrophobic regions interacting with the lipid bilayer. The “carpet” model (D) proposes that peptides aggregate parallel to the lipid bilayer, coating local areas in a “carpet”-like fashion. At a given threshold concentration, this is thought to result in a detergent-like activity, causing formation of micelles and membrane pores. The mechanisms of action of peptides which do not act by permeabilizing the bacterial membrane are depicted in panels E to I. The antimicrobial peptides buforin II, pleurocidin, and dermaseptin have all been shown to inhibit DNA and RNA synthesis at their MICs without destabilizing the membrane (E). Protein synthesis is another macromolecular target for antibacterial peptides such as indolicidin and PR-39, which have been shown to decrease the rate of protein synthesis in target bacterial cells (F). Several antibacterial peptides have been shown to act on other intracellular target processes, such as enzymatic activity. The ATPase activity of DnaK, an enzyme involved in chaperone-assisted protein folding, is targeted by pyrrhocidin (G), while inhibition of enzymes involved in the modification of aminoglycosides has also been demonstrated (H). Antimicrobial peptides can also target the formation of structural components, such as the cell wall (I). Lantibiotics such as nisin and mersacidin can bind to and inhibit, respectively, the transglycosylation of lipid II, which is necessary for the synthesis of peptidoglycan.