The increase of pathogens being resistant to antibiotics represents a global health problem
and therefore it is a pressing need to develop antibiotics with novel mechanisms of action. Host defense
peptides, which have direct antimicrobial activity (also termed antimicrobial peptides) or immune
modulating activity, are valuable template structures for the development of such compounds.
Antimicrobial peptides exhibit remarkably different structures as well as biological activity profiles
with multiple targets. A large fraction of these peptides interfere physically with the cell membrane of
bacteria (focus of this review), but can also translocate into the cytosol, where they interact with nucleic
acids, ribosomes and proteins. Several potential interaction sites have to be considered on the
route of the peptides from the environment to the cytoplasmic membrane. Translocation of peptides
through the cell wall may not be impaired by the thick but relatively porous peptidoglycan layer. However,
interaction with lipopolysaccharides of the outer membrane of Gram-negative bacteria and
(lipo)teichoic acids of Gram-positive bacteria may reduce the effective concentration at the cytoplasmic
membrane, where supposedly the killing event takes place. On a molecular level several mechanisms
are discussed, which are important for the rational design of improved antimicrobial compounds:
toroidal pore formation, carpet model (coverage of membrane surface by peptides), interfacial
activity, void formation, clustering of lipids and effects of membrane curvature. In summary, many of
these models just represent special cases that can be interrelated to each other and depend on both the
nature of lipids and peptides.
Keywords: Antimicrobial resistance, Cell envelope, Host defense peptides, Interfacial activity, Membrane permeabilization,
Membrane composition, Membrane curvature, Pore formation.
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