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JAC Advance Access published online on January 16, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh083
© 2004 by The British Society for Antimicrobial Chemotherapy
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© 2004 The British Society for Antimicrobial Chemotherapy

Original article

In vitro activity and mode of action of diastereomeric antimicrobial peptides against bacterial clinical isolates

U. Pag 1 , M. Oedenkoven 1 , N. Papo 2 , Z. Oren 2 , Y. Shai 2 , and H.-G. Sahl 1 *

1 Institut für Medizinische Mikrobiologie und Immunologie der Universität Bonn, D-53105 Bonn, Germany;
2 Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100 Israel

* Corresponding author. E-mail: sahl{at}mibi03.meb.uni-bonn.de.

Received 22 September 2003 ; revised 19 November 2003 ; accepted 20 November 2003

Abstract

Objectives: Increasing resistance of pathogenic bacteria to antibiotics is a severe problem in health care and has intensified the search for novel drugs. Cationic antibacterial peptides are the most abundant antibiotics in nature and have been frequently proposed as new anti-infective agents. Here, a group of diastereomeric (containing D- and L-amino acids) peptides is studied regarding their potency against multiply resistant clinical isolates and their modes of action against Gram-positive cocci.

Methods: MIC determinations and chequerboard titrations followed established procedures. Mode of action studies included killing kinetics and a series of experiments designed to characterize the impact of the diastereomeric peptides on bacterial membranes.

Results: The tested diastereomers displayed high antimicrobial and broad spectrum activity with amphipathic-2D being the most active peptide. Synergic activities were observed with individual strains. Mode of action studies clearly demonstrated that the cytoplasmic membrane is a primary target for the peptides and that membrane disruption constitutes a significant bactericidal activity for the major fraction of a bacterial population. However, depending on the indicator strain, the results also suggest that additional molecular events contribute to the overall activity.

Keywords: synergic activities, membrane permeabilization, intracellular targets
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