As bacteria become resistant to more antibiotics, researchers are revisiting one of the oldest defence systems in biology. Antimicrobial peptides (AMPs) are made by nearly every form of life, and bacteria have found them harder to resist than many conventional antibiotics.
What they look like
Most AMPs are short, usually 10–50 residues. They share two key features:
- Positive charge, from lysine and arginine residues. Bacterial membranes are more negatively charged than animal cell membranes, which gives AMPs a degree of selectivity.
- Amphipathic shape: one face of the peptide is water-loving and the other is fat-loving, so it can slot into membranes.
Where they come from
| Source | Examples |
|---|---|
| Insects | Cecropins, discovered in silk moths by Hans Boman's group in 1981 |
| Amphibians | Magainins, isolated from African clawed frog skin by Michael Zasloff in 1987 |
| Humans | Defensins and the cathelicidin LL-37, found on skin, in the airways and in white blood cells |
| Bacteria | Nisin, a lantibiotic used as a food preservative (E234) |
How they kill bacteria
Most AMPs attack the bacterial membrane. Researchers describe several models:
- Barrel-stave: peptides line up like the staves of a barrel to form a pore.
- Toroidal pore: peptides and membrane lipids bend together to form a pore.
- Carpet: peptides coat the surface until the membrane breaks apart, a bit like a detergent.
Some AMPs also cross the membrane and interfere with processes inside the cell, and many also influence the host immune system.
Why resistance is slower to develop
Many antibiotics block one specific enzyme, which a single mutation can alter. Changing the basic make-up of a whole membrane is much harder for a bacterium. Resistance to AMPs does occur, but it usually develops more slowly.
The hurdles
- Toxicity: at higher concentrations, some AMPs also damage human cells, measured as haemolysis of red blood cells.
- Stability: proteases in the body can break them down quickly.
- Salt and serum sensitivity: some AMPs lose activity in body fluids.
- Cost: making peptides at scale is more expensive than making small molecules.
Current research addresses these hurdles with D-amino acids, cyclisation, peptidomimetics and machine-learning design. Some peptide-based antibiotics, such as the polymyxins and daptomycin, are already used clinically as treatments of last resort.
Related articles
- Cyclic peptides in nature
- Display technologies: searching billions of peptides at once
- From lab to licence: how peptide medicines are developed
Sources and further reading
- Steiner H et al. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature 1981;292:246–248. doi:10.1038/292246a0 · PMID: 7019715
- Zasloff M. Magainins, a class of antimicrobial peptides from Xenopus skin. PNAS 1987;84:5449–5453. doi:10.1073/pnas.84.15.5449 · PMID: 3299384
- Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002;415:389–395. doi:10.1038/415389a · PMID: 11807545
- Hancock REW, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 2006;24:1551–1557. doi:10.1038/nbt1267 · PMID: 17160061