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.
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, translocated antimicrobial peptides can alter the cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibit protein synthesis or inhibit enzymatic activity, all of which can rapidly kill microorganisms.
Microorganisms also use a number of resistance strategies to circumvent antimicrobial peptide killing, and these mechanisms have relevance to the concepts presented in this review. These bacterial strategies counter mechanisms of antimicrobial peptide attachment, peptide insertion and membrane permeability.
Recognition that antimicrobial peptides induce transmembrane pores and have other intracellular targets that are capable of rapidly killing microorganisms will facilitate the development, design and synthesis of more efficient, broad-spectrum therapeutic antimicrobial peptides.
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Kim Brogden's laboratory is supported by the National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH).
The author declares no competing financial interests.
Here, used to describe peptides containing both hydrophilic and hydrophobic amino acid residues, where spatial separation of these residues facilitates their attachment and insertion into membranes.
- LIQUID-CRYSTALLINE STATE
The state and temperature at which hydrocarbon tails of the lipid bilayers are fluid and can move. In most biomembranes, the lipids are in the liquid-crystalline state under physiological conditions.
- NEUTRON IN-PLANE SCATTERING
A neutron-diffraction pattern of a peptide and membrane sample with the multilayer sample oriented normal to the incident neutron beam.
- NEUTRON OFF-PLANE SCATTERING
A neutron-diffraction pattern of a peptide and membrane sample in a sandwiched multilayer sample oriented at an oblique angle with respect to the incident neutron beam, so that the entire low-angle diffraction pattern can be recorded by the area detector at one sample-to-detector distance.
- COULOMB ENERGY
The energy that one stationary, electrically charged substance of small volume exerts on another. For example, in pores formed from numerous cationic peptides, the Coulomb energy would be so high that pore formation would not be possible unless the positive charges are effectively screened when the peptides insert into the membrane containing anionic phospholipids.
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Brogden, K. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?. Nat Rev Microbiol 3, 238–250 (2005). https://doi.org/10.1038/nrmicro1098
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