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Published online before print December 6, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0804452


Revised October 29, 2004.
Accepted for publication November 3, 2004.

Article

Mammalian defensins: structures and mechanism of antibiotic activity

Hans-Georg Sahl ^*@, Ulrike Pag ^*, Sonja Bonness ^*, Sandra Wagner ^*, Nikolinka Antcheva , and Alessandro Tossi

*Institute for Medical Microbiology and Immunology, University of Bonn, Germany; and Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, Italy

^@ To whom correspondence should be addressed. E-mail: sahl{at}mibi03.meb.uni-bonn.de.

	Abstract

Antibiotic peptides are important effector molecules in host-parasite interactions throughout the living world. In vertebrates, they function in first-line host defense by antagonizing a wide range of microbes including bacteria, fungi, and enveloped viruses. The antibiotic activity is thought to be based on their cationic, amphipathic nature, which enables the peptides to impair vital membrane functions. Molecular details for such activities have been elaborated with model membranes; however, there is increasing evidence that these models may not reflect the complex processes involved in the killing of microbes. For example, the overall killing activity of the bacterial peptide antibiotic nisin is composed of independent activities such as the formation of target-mediated pores, inhibition of cell-wall biosynthesis, formation of nontargeted pores, and induction of autolysis. We studied the molecular modes of action of human defense peptides and tried to determine whether they impair membrane functions primarily and whether additional antibiotic activities may be found. We compared killing kinetics, solute efflux kinetics, membrane-depolarization assays, and macromolecular biosynthesis assays and used several strains of Gram-positive cocci as test strains. We found that membrane depolarization contributes to rapid killing of a significant fraction of target cells within a bacterial culture. However, substantial subpopulations appear to survive the primary effects on the membrane. Depending on individual strains and species and peptide concentrations, such subpopulations may resume growth or be killed through additional activities of the peptides. Such activities can include the activation of cell-wall lytic enzymes, which appears of particular importance for killing of staphylococcal strains.

Key Words: human -defensin 3 • membrane depolarization • staphylococci

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