Cyclic antimicrobial R-, W-rich peptides: the role of peptide structure and E. coli outer and inner membranes in activity and the mode of action

This study compares the effect of cyclic R-, W-rich peptides with variations in amino acid sequences and sizes from 5 to 12 residues upon Gram negative and Gram positive bacteria as well as outer membrane-deficient and LPS mutant Escherichia coli ( E. coli ) strains to analyze the structural determi...

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Bibliographic Details
Published in:European biophysics journal 2011-04, Vol.40 (4), p.515-528
Main Authors: Junkes, Christof, Harvey, Richard D., Bruce, Kenneth D., Dölling, Rudolf, Bagheri, Mojtaba, Dathe, Margitta
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Anti-Infective Agents - chemistry
Anti-Infective Agents - pharmacology
Antimicrobial agents
Biochemistry
Biological and Medical Physics
Biomedical and Life Sciences
Biophysics
Calorimetry
Cell Biology
Cell Membrane - chemistry
Cell Membrane - drug effects
Cell Membrane - metabolism
Cell Membrane Permeability - drug effects
Cellular biology
Chromatography, High Pressure Liquid
Circular Dichroism
E coli
Escherichia coli
Escherichia coli - chemistry
Escherichia coli - metabolism
Eukaryotic Cells - chemistry
Eukaryotic Cells - metabolism
Life Sciences
Lipids
Lipopolysaccharides - chemistry
Lipopolysaccharides - metabolism
Liposomes - chemistry
Liposomes - metabolism
Membrane Biology
Membranes
Microbial Sensitivity Tests
Molecular Sequence Data
Nanotechnology
Neurobiology
Original Paper
Peptides
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
Phosphatidylethanolamines - chemistry
Phosphatidylethanolamines - metabolism
Phosphatidylglycerols - chemistry
Phosphatidylglycerols - metabolism
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Summary:This study compares the effect of cyclic R-, W-rich peptides with variations in amino acid sequences and sizes from 5 to 12 residues upon Gram negative and Gram positive bacteria as well as outer membrane-deficient and LPS mutant Escherichia coli ( E. coli ) strains to analyze the structural determinants of peptide activity. Cyclo-RRRWFW (c-WFW) was the most active and E. coli -selective sequence and bactericidal at the minimal inhibitory concentration (MIC). Removal of the outer membrane distinctly reduced peptide activity and the complete smooth LPS was required for maximal activity. c-WFW efficiently permeabilised the outer membrane of E. coli and promoted outer membrane substrate transport. Isothermal titration calorimetric studies with lipid A-, rough-LPS (r-LPS)- and smooth-LPS (s-LPS)-doped POPC liposomes demonstrated the decisive role of O-antigen and outer core polysaccharides for peptide binding and partitioning. Peptide activity against the inner E. coli membrane (IM) was very low. Even at a peptide to lipid ratio of 8/1, c-WFW was not able to permeabilise a phosphatidylglycerol/phosphatidylethanolamine (POPG/POPE) bilayer. Low influx of propidium iodide (PI) into bacteria confirmed a low permeabilising ability of c-WFW against PE-rich membranes at the MIC. Whilst the peptide effect upon eukaryotic cells correlated with the amphipathicity and permeabilisation of neutral phosphatidylcholine bilayers, suggesting a membrane disturbing mode of action, membrane permeabilisation does not seem to be the dominating antimicrobial mechanism of c-WFW. Peptide interactions with the LPS sugar moieties certainly modulate the transport across the outer membrane and are the basis of the E. coli selectivity of this type of peptides.
ISSN:0175-7571
1432-1017
DOI:10.1007/s00249-011-0671-x