Amphiphilic cationic β(3R3)-peptides: membrane active peptidomimetics and their potential as antimicrobial agents.
We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β(3R3)-peptides, and evaluate their potential as antimicrobial agents. The design criteria, the building block and oligomer synthesis as well as a detailed structure-activity relationship (SAR) study are reported. Specifically, infrared reflection absorption spectroscopy (IRRAS) was employed to investigate structural features of amphiphilic cationic β(3R3)-peptide sequences at the hydrophobic/hydrophilic air/liquid interface. Furthermore, Langmuir monolayers of anionic and zwitterionic phospholipids have been used to model the interactions of amphiphilic cationic β(3R3)-peptides with prokaryotic and eukaryotic cellular membranes in order to predict their membrane selectivity and elucidate their mechanism of action. Lastly, antimicrobial activity was tested against Gram-positive M. luteus and S. aureus as well as against Gram-negative E. coli and P. aeruginosa bacteria along with testing hemolytic activity and cytotoxicity. We found that amphiphilic cationic β(3R3)-peptide sequences combine high and selective antimicrobial activity with exceptionally low cytotoxicity in comparison to values reported in the literature. Overall, this study provides further insights into the SAR of antimicrobial peptides and peptidomimetics and indicates that amphiphilic cationic β(3R3)-peptides are strong candidates for further development as antimicrobial agents with high therapeutic index.
Department of Biomolecular Systems and ‡Department of Interfaces, Research Campus Golm, Max Planck Institute of Colloids and Interfaces , 14424 Potsdam, Germany.
Simone
S
Mosca
Janos
J
Keller
Nahid
N
Azzouz
Stefanie
S
Wagner
Alexander
A
Titz
Peter H
PH
Seeberger
Gerald
G
Brezesinski
Laura
L
Hartmann
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D016982:Micrococcus luteus / Q000187:drug effects; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057786:Peptidomimetics; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002412:Cations; D010455:Peptides; D057786:Peptidomimetics; D013501:Surface-Active Agents