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

Analysis of in vitro activities and modes of action of synthetic antimicrobial peptides derived... ObjectivesCationic 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 -helical AMPs, which were then analysed regarding efficacy against clinical isolates and antibiotic mechanisms.MethodsEfficacy 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 (90 of) the S. aureus N315 genome and AMP P16(6E).ResultsThe 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.ConclusionsThe 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

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

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References (39)

Publisher
Oxford University Press
Copyright
© Published by Oxford University Press.
Subject
Original research
ISSN
0305-7453
eISSN
1460-2091
DOI
10.1093/jac/dkm479
pmid
18174202
Publisher site
See Article on Publisher Site

Abstract

ObjectivesCationic 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 -helical AMPs, which were then analysed regarding efficacy against clinical isolates and antibiotic mechanisms.MethodsEfficacy 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 (90 of) the S. aureus N315 genome and AMP P16(6E).ResultsThe 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.ConclusionsThe 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.

Journal

Journal of Antimicrobial Chemotherapy – Oxford University Press

Published: Feb 3, 2008

Keywords: Keywords membrane permeabilization intracellular targets transcriptional profiling microarray

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