Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?

Antimicrobial peptides are an abundant and diverse group of molecules that are produced by many tissues and cell types in a variety of invertebrate, plant and animal species. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by 'barrel-stave', 'carpet' or 'toroidal-pore' mechanisms. Although these models are helpful for defining mechanisms of antimicrobial peptide activity, their relevance to how peptides damage and kill microorganisms still need to be clarified. Recently, there has been speculation that transmembrane pore formation is not the only mechanism of microbial killing. In fact several observations suggest that translocated peptides can alter cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibit protein synthesis or inhibit enzymatic activity. In this review the different models of antimicrobial-peptide-induced pore formation and cell killing are presented. Key Points Antimicrobial peptides are abundant and produced by many tissues and cell types in a variety of invertebrate, plant and animal species. So far, more than 880 different antimicrobial peptides have been identified or predicted from their nucleic acid sequences. These peptides are often divided into families on the basis of their unique amino acid compositions and structures. The families include anionic peptides, helical cationic peptides (which are short, lack cysteine residues and sometimes have a hinge or 'kink' in the middle), peptides rich in amino acids such as proline, arginine, phenylalanine or tryptophan, and anionic and cationic peptides, which contain cysteine, have disulphide bonds and form stable β-sheets. Assessing the interaction of antimicrobial peptides with phospholipids in model membranes provides some insight into their mechanisms of activity. The attraction, attachment, insertion and orientation of the peptide in the lipid bilayer can be determined by X-ray crystallography, NMR spectroscopy in solution and in the presence of lipid bilayers, and FTIR, Raman, fluorescence and CD optical spectroscopies. They insert into well-defined membrane bilayers, forming pores by 'barrel-stave', 'carpet' or 'toroidal-pore' mechanisms. Although the formation of transmembrane pores eventually leads to the lysis of microbial cells, there is a growing speculation that this is not the sole mechanism of microbial killing. In fact, transloca