Antimicrobial peptides (AMPs) represent one of the most ancient and universal defense mechanisms against pathogens.
Human AMP Classes
Defensins **Cysteine-rich peptides with rigid β-sheet structures**
- **α-Defensins (HNP1-4, HD5-6)** — Found in neutrophils and intestinal Paneth cells
- **β-Defensins (hBD1-4)** — Expressed by epithelial cells throughout the body
- 29-45 amino acids
- 3 disulfide bonds
- Stable, protease-resistant structure
Cathelicidins **The sole human cathelicidin is LL-37**
- 37 amino acids, α-helical structure
- Stored as inactive proform (hCAP18) in neutrophils
- Cleaved to active LL-37 upon degranulation
- Broad-spectrum antimicrobial
- Immunomodulatory (chemotaxis, wound healing)
- Anti-biofilm activity
Other Human AMPs - **Histatins** — Salivary antifungal peptides - **Dermcidin** — Anionic peptide in sweat - **Lactoferricin** — Derived from lactoferrin
Mechanisms of Action
Membrane Disruption AMPs exploit the difference between bacterial and human membranes:
| Feature | Bacterial Membranes | Human Membranes |
|---|---|---|
| Net charge | Strongly anionic | Neutral (outer) |
| Cholesterol | None | Present |
| Phospholipids | PS, PG exposed | PC, SM outer |
- **Barrel-stave** — Peptides form transmembrane pores
- **Toroidal pore** — Peptides and lipids curve together
- **Carpet model** — Peptides coat and dissolve membrane
Intracellular Targets Some AMPs penetrate cells to: - Bind DNA and RNA - Inhibit protein synthesis - Disrupt cell division
Immunomodulation Beyond direct killing, AMPs: - Recruit immune cells (chemotaxis) - Neutralize LPS (prevent sepsis) - Promote wound healing - Modulate inflammation
Bacterial Resistance Mechanisms
- **Surface remodeling** — Reduce membrane negative charge
- **Proteolytic degradation** — Secrete peptidases
- **Efflux pumps** — Export peptides
- **Biofilm formation** — Physical barrier
Therapeutic Potential
- Toxicity to host cells at high concentrations
- Susceptibility to host proteases
- High production costs
- **Peptidomimetics** — Synthetic mimics with improved stability
- **Stapled peptides** — Constrained structures resistant to proteases
- **Hybrid molecules** — AMPs conjugated to conventional antibiotics