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J. Biol. Chem., Vol. 277, Issue 37, 33913-33921, September 13, 2002
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From the The search for antibiotics with a new
mode of action led to numerous studies on antibacterial peptides. Most
of the studies were carried out with L-amino acid
peptides possessing amphipathic
The Consequence of Sequence Alteration of an Amphipathic
-Helical Antimicrobial Peptide and Its Diastereomers*
,,¶
Department of Biological Chemistry, The
Weizmann Institute of Science, Rehovot, 76100 Israel and the
§ Institute for Medical Microbiology and Immunology,
University of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany
-helix or 
-sheet structures,
which are known to be important for biological activities. Here we
compared the effect of significantly altering the sequence of an
amphipathic -helical peptide (15 amino acids long) and its
diastereomer (composed of both L- and D-amino
acids) regarding their structure, function, and interaction with model
membranes and intact bacteria. Interestingly, the effect of sequence
alteration on biological function was similar for the
L-amino acid peptides and the diastereomers, despite some differences in their structure in the membrane as revealed by attenuated total reflectance Fourier-transform infrared spectroscopy. However, whereas the all L-amino acid peptides were highly
hemolytic, had low solubility, lost their activity in serum, and were
fully cleaved by trypsin and proteinase K, the diastereomers were
nonhemolytic and maintained full activity in serum. Furthermore,
sequence alteration allowed making the diastereomers either fully,
partially, or totally protected from degradation by the enzymes.
Transmembrane potential depolarization experiments in model membranes
and intact bacteria indicate that although the killing mechanism of the
diastereomers is via membrane perturbation, it is also dependent on
their ability to diffuse into the inner bacterial membrane. These data
demonstrate the advantage of the diastereomers over their all
L-amino acid counterparts as candidates for developing a
repertoire of new target antibiotics with a potential for systemic use.
*
This work was supported by the European Community Project
Number QLK2-2000-00411.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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