Journal article
Side Chain Hydrophobicity Modulates Therapeutic Activity and Membrane Selectivity of Antimicrobial Peptide Mastoparan-X
Department of Chemistry, Technical University of Denmark1
Physical and Biophysical Chemistry, Department of Chemistry, Technical University of Denmark2
Center for Nanomedicine and Theranostics, Centers, Technical University of Denmark3
Department of Micro- and Nanotechnology, Technical University of Denmark4
Colloids and Biological Interfaces, Department of Micro- and Nanotechnology, Technical University of Denmark5
The discovery of new anti-infective compounds is stagnating and multi-resistant bacteria continue to emerge, threatening to end the "antibiotic era''. Antimicrobial peptides (AMPs) and lipo-peptides such as daptomycin offer themselves as a new potential class of antibiotics; however, further optimization is needed if AMPs are to find broad use as antibiotics.
In the present work, eight analogues of mastoparan-X (MPX) were investigated, having side chain modifications in position 1, 8 and 14 to modulate peptide hydrophobicity. The self-association properties of the peptides were characterized, and the peptide-membrane interactions in model membranes were compared with the bactericidal and haemolytic properties.
Alanine substitution at position 1 and 14 resulted in higher target selectivity (red blood cells versus bacteria), but also decreased bactericidal potency. For these analogues, the gain in target selectivity correlated to biophysical parameters showing an increased effective charge and reduction in the partitioning coefficient for membrane insertion.
Introduction of an unnatural amino acid, with an octyl side chain by amino acid substitution, at positions 1, 8 and 14 resulted in increased bactericidal potency at the expense of radically reduced membrane target selectivity. Overall, optimized membrane selectivity or bactericidal potency was achieved by changes in side chain hydrophobicity of MPX.
However, enhanced potency was achieved at the expense of selectivity and vice versa in all cases.
Language: | English |
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Publisher: | Public Library of Science |
Year: | 2014 |
Pages: | e91007 |
ISSN: | 19326203 |
Types: | Journal article |
DOI: | 10.1371/journal.pone.0091007 |
ORCIDs: | Henriksen, Jonas Rosager and Andresen, Thomas Lars |
ANTIBACTERIAL BINDING INTERFACES LIPID-MEMBRANES LIPOPEPTIDES MAGAININ 2 AMIDE MODEL MULTIDISCIPLINARY PORE FORMATION THERMODYNAMICS TITRATION CALORIMETRY
Alkylation Amino Acid Sequence Anti-Infective Agents Cell Membrane Hemolysis Humans Hydrophobic and Hydrophilic Interactions Intercellular Signaling Peptides and Proteins Medicine Molecular Sequence Data Peptides Q R Science Structure-Activity Relationship Substrate Specificity mastoparan X