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Title: Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes

In this study, 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.
 [1] ;  [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [3] ;  [2] ;  [1]
  1. Illinois Inst. of Technology, Chicago, IL (United States)
  2. Technical Univ. of Denmark, Lyngby (Denmark)
  3. Argonne National Lab. (ANL), Lemont, IL (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357; W-31-109-ENG-38; R01 AI073892; W911NF-09-1-378; 09-065902; 09-066098; 10-080907; W-31-109-Eng-38
Published Article
Journal Name:
Biochimica et Biophysica Acta. Biomembranes
Additional Journal Information:
Journal Volume: 1838; Journal Issue: 10; Related Information: Open Archive; Journal ID: ISSN 0005-2736
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; antimicrobial peptidomimetics; peptide-peptoid chimeras; guanidinium cation; bacterial membrane; phosphatidylglycerol; X-ray scattering
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1225369