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J Antimicrob Chemother. 2008 Feb;61(2):341-52. doi: 10.1093/jac/dkm479. Epub 2008 Jan 3.

Analysis of in vitro activities and modes of action of synthetic antimicrobial peptides derived from an alpha-helical 'sequence template'.

Author information

1
Institute for Medical Microbiology, Immunology and Parasitology-Pharmaceutical Microbiology Section, University of Bonn, 53105 Bonn, Germany.

Abstract

OBJECTIVES:

Cationic antimicrobial peptides (AMPs) are indispensable components of innate immune systems and promising candidates for novel anti-infective strategies. We rationally designed a series of peptides based on a template derived from known alpha-helical AMPs, which were then analysed regarding efficacy against clinical isolates and antibiotic mechanisms.

METHODS:

Efficacy tests included standard MIC and synergy assays. Whole cell assays with staphylococcal strains included killing kinetics, efflux experiments and determination of membrane depolarization. The transcriptional response of AMP-treated Staphylococcus aureus SG511 was analysed using a Scienion genomic microarray covering (approximately 90% of) the S. aureus N315 genome and AMP P16(6|E).

RESULTS:

The AMPs showed remarkable broad-spectrum activity against bacteria and fungi regardless of any pre-existing antibiotic resistance mechanism. Whole cell assays indicated that the AMPs target the cytoplasmic membrane; however, significant membrane leakage and depolarization was only observed with a standard laboratory test strain. Transcriptional profiling identified up-regulation of putative efflux pumps and of aerobic energy generation mechanisms as major counter activities. Important components of the staphylococcal cell wall stress stimulon were up-regulated and the lipid metabolism was also affected.

CONCLUSIONS:

The broad spectrum activity of amphiphilic helical AMPs is based on multiple stresses resulting from interactions with microbial membranes; however, rather than killing through formation of pores, the AMPs appear to interfere with the coordinated and highly dynamic functioning of membrane bound multienzyme complexes such as electron transport chains and cell wall or lipid biosynthesis machineries.

PMID:
18174202
DOI:
10.1093/jac/dkm479
[Indexed for MEDLINE]
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