TY - JOUR
T1 - Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes
AU - Andreev, Konstantin
AU - Bianchi, Christopher
AU - Laursen, Jonas Striegler
AU - Citterio, Linda
AU - Hein-Kristensen, Line
AU - Gram, Lone
AU - Kuzmenko, Ivan
AU - Olsen, Christian A
AU - Gidalevitz, David
N1 - Copyright © 2014 Elsevier B.V. All rights reserved.
PY - 2014/10
Y1 - 2014/10
N2 - Antimicrobial peptides or their synthetic mimics are a promising class of potential new antibiotics. Herein we assess the effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial α-peptide-β-peptoid chimeras. Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) were used to model cytoplasmic membranes of both Gram-positive and Gram-negative bacteria, while lipopolysaccharide Kdo2-lipid A monolayers were mimicking the outer membrane of Gram-negative species. We report the results of the measurements using an array of techniques, including high-resolution synchrotron surface X-ray scattering, epifluorescence microscopy, and in vitro antimicrobial activity to study the molecular mechanisms of peptidomimetic interaction with bacterial membranes. We found guanidino group-containing chimeras to exhibit greater disruptive activity on DPPG monolayers than the amino group-containing analogues. However, this effect was not observed for lipopolysaccharide monolayers where the difference was negligible. Furthermore, the addition of the nitrobenzoxadiazole fluorophore did not reduce the insertion activity of these antimicrobials into both model membrane systems examined, which may be useful for future cellular localization studies.
AB - Antimicrobial peptides or their synthetic mimics are a promising class of potential new antibiotics. Herein we assess the effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial α-peptide-β-peptoid chimeras. Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) were used to model cytoplasmic membranes of both Gram-positive and Gram-negative bacteria, while lipopolysaccharide Kdo2-lipid A monolayers were mimicking the outer membrane of Gram-negative species. We report the results of the measurements using an array of techniques, including high-resolution synchrotron surface X-ray scattering, epifluorescence microscopy, and in vitro antimicrobial activity to study the molecular mechanisms of peptidomimetic interaction with bacterial membranes. We found guanidino group-containing chimeras to exhibit greater disruptive activity on DPPG monolayers than the amino group-containing analogues. However, this effect was not observed for lipopolysaccharide monolayers where the difference was negligible. Furthermore, the addition of the nitrobenzoxadiazole fluorophore did not reduce the insertion activity of these antimicrobials into both model membrane systems examined, which may be useful for future cellular localization studies.
KW - Anti-Infective Agents
KW - Bacteria
KW - Cell Membrane
KW - Guanidine
KW - Lipopolysaccharides
KW - Peptidomimetics
KW - Phosphatidylglycerols
U2 - 10.1016/j.bbamem.2014.05.022
DO - 10.1016/j.bbamem.2014.05.022
M3 - Journal article
C2 - 24878450
SN - 0005-2736
VL - 1838
SP - 2492
EP - 2502
JO - B B A - Biomembranes
JF - B B A - Biomembranes
IS - 10
ER -