Antimicrobial Peptides and Natural Host Defenses

Core Idea

Antimicrobial peptides (defensins, cathelicidins, histatins) and lysozyme are innate immune molecules that kill or inhibit bacteria and fungi. These molecules disrupt membranes, inhibit cell-wall synthesis, or target nucleic acids. Resistance to these defenses drives bacterial pathogenesis and biofilm formation.

Explainer

Before the adaptive immune system even knows an infection is underway, the body has already deployed a chemical arsenal at every surface exposed to the environment. You know from your study of innate immunity that the first line of defense is rapid and nonspecific. Antimicrobial peptides (AMPs) and lysozyme are the molecular weapons of that first line — proteins that kill microbes directly, without needing to recognize specific antigens or wait for lymphocyte activation.

Lysozyme is the simplest to understand. It is an enzyme found in tears, saliva, nasal secretions, and the granules of neutrophils. Its target is peptidoglycan, the rigid mesh that gives bacterial cell walls their structural integrity. Lysozyme cleaves the β-1,4 glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine — the same bond that holds peptidoglycan chains together. Without an intact wall, bacteria in a hypotonic environment (like tears or saliva) undergo osmotic lysis. Gram-positive bacteria, with their thick exposed peptidoglycan layer, are especially vulnerable. Gram-negative bacteria gain partial protection from their outer membrane, which shields the thinner peptidoglycan layer beneath.

Antimicrobial peptides work differently. Defensins — small, cationic (positively charged) peptides produced by epithelial cells and neutrophils — exploit a fundamental difference between microbial and host cell membranes. Bacterial membranes are rich in negatively charged phospholipids (like phosphatidylglycerol), while mammalian cell membranes have their negative charges mostly on the inner leaflet, with neutral cholesterol stabilizing the outer surface. Defensins are electrostatically attracted to bacterial membranes, insert into the lipid bilayer, and form pores that collapse the membrane potential and cause cell death. Cathelicidins (such as LL-37 in humans) work similarly but also have immunomodulatory roles — they recruit immune cells, promote wound healing, and can neutralize bacterial lipopolysaccharide. Histatins, found in saliva, are particularly effective against fungi like *Candida*, disrupting mitochondrial function in yeast cells.

The evolutionary pressure these defenses exert is enormous. Pathogens that successfully colonize human tissues have evolved countermeasures: modifying their surface charge to repel cationic peptides, producing proteases that degrade AMPs, or forming biofilms — structured communities encased in a protective matrix that AMPs cannot easily penetrate. Understanding this arms race is essential because it explains why certain organisms are pathogenic while closely related species are harmless commensals. It also explains why the loss of AMP production — through genetic defects, burns, or chronic disease — dramatically increases susceptibility to infection at epithelial surfaces.