Transcript Tan2
The focus of infection is surrounded by epithelial cells that express bdefensins
Courtesy of Lide Liu (Univ. of California, Los Angeles)
Antimicrobial
Peptides
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Antimicrobial peptides are evolutionarily ancient weapons. Their widespread
distribution and abundance (> 800 eukaryotic peptides described) throughout the
animal and plant kingdoms suggests that antimicrobial peptides have served a
fundamental role in the successful evolution of complex multicellular organisms.
The fundamental structural principle underlying all classes is the ability of the
molecule to adopt a shape in which clusters of hydrophobic and cationic amino acids
are spatially organized in discrete sectors of the molecule ('amphipathic' design).
All antimicrobial peptides are derived from larger precursors, including a signal
sequence. Post-translational modifications include proteolytic processing, and in
some cases glycosylation, carboxy-terminal amidation and amino-acid isomerization
and halogenation.
Some peptides are derived by proteolysis from larger proteins, such as buforin II from
histone 2A and lactoferricin from lactoferrin.
Most multicellular organisms express a cocktail comprising multiple peptides from
several of these structural classes within their 'defensive' tissues.
Antimicrobial peptides from
plants and invertebrates
Schroder-CMLS-99
Mammalian Defensins
Yang et al, Trends Immunol, 02
In human, Paneth Cells in Crypts of
Leiberkuhn secrete a-defensins or
cryptins.
proHD5 is proteolytically cleaved
extrcellularly by trypsin. It also
highlights that this enzyme has other
nondigestive function.
Unmodified proHD5 also has
antimicrobial activity, especially when
tested against Gram-positive L.
monocytogenes.
The differential antibacterial activity
between the HD5 forms that exist in vivo
suggests that proteolytic processing
could be a mechanism that diversifies the
spectrum of antibiotic activity from a
single antimicrobial gene product.
Basis of Specificity of Antimicrobial Peptides
The Shai–Matsuzaki–Huang (SMH) model for AMP activity
How do antimicrobial peptides actually kill
microbes?
• The creation of physical holes that cause cellular contents
to leak out [BioPhys. J. 79, 2002 (2000)].
• Fatal depolarization of the normally energized bacterial
membrane [PNAS 86, 6597 (1989)].
• The activation of deadly processes, such as autolysis, by
the induction of hydrolases that degrade the cell wall
[Arch. Microbiol. 141, 249 (1985)].
• The scrambling of the usual distribution of lipids between
the leaflets of the bilayer, resulting in disturbance of
membrane functions [BBA 1462, 1 (1999)].
• The damaging of critical intracellular targets after
internalization of the peptide. For example, the peptide
pyrrhocoricin, inhibits ATPase actions of DnaK and
prevent chaperone-assisted protein folding [Biochem. 40,
3016 (2001)].
Cathelicidins
• Processed by neutrophil elastase in the extracellular milieu.
• Extracellular proteolytic activation of AMPs is also conserved in lower
vertebrates and insects.
• Antimicrobial activity is synergistic with lysozyme and lactoferrin,
PNAS 95(1988),9541
• Activity is dependent on the concentration of NaCl (activity diminishes
4- to 5-fold as the total concentration of NaCl is elevated from 60 to
155 mM), PNAS 95(1988),9541.
Mouse Cathelicidin, CRAMP, Protects the Skin from
Group A Streptococcus
Nizet et al, Nature 2001
Important cytokines secreted by macrophages in response to bacterial products