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

Abstract

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.

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1227320
Alternate Identifier(s):
OSTI ID: 1225369
Grant/Contract Number:  
W-31-109-Eng-38; AC02-06CH11357; W-31-109-ENG-38; R01 AI073892; W911NF-09-1-378; 09-065902; 09-066098; 10-080907
Resource Type:
Published Article
Journal Name:
Biochimica et Biophysica Acta. Biomembranes
Additional Journal Information:
Journal Name: Biochimica et Biophysica Acta. Biomembranes Journal Volume: 1838 Journal Issue: 10; Journal ID: ISSN 0005-2736
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; antimicrobial peptidomimetics; peptide-peptoid chimeras; guanidinium cation; bacterial membrane; phosphatidylglycerol; X-ray scattering

Citation Formats

Andreev, Konstantin, Bianchi, Christopher, Laursen, Jonas S., Citterio, Linda, Hein-Kristensen, Line, Gram, Lone, Kuzmenko, Ivan, Olsen, Christian A., and Gidalevitz, David. Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes. Netherlands: N. p., 2014. Web. https://doi.org/10.1016/j.bbamem.2014.05.022.
Andreev, Konstantin, Bianchi, Christopher, Laursen, Jonas S., Citterio, Linda, Hein-Kristensen, Line, Gram, Lone, Kuzmenko, Ivan, Olsen, Christian A., & Gidalevitz, David. Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes. Netherlands. https://doi.org/10.1016/j.bbamem.2014.05.022
Andreev, Konstantin, Bianchi, Christopher, Laursen, Jonas S., Citterio, Linda, Hein-Kristensen, Line, Gram, Lone, Kuzmenko, Ivan, Olsen, Christian A., and Gidalevitz, David. Wed . "Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes". Netherlands. https://doi.org/10.1016/j.bbamem.2014.05.022.
@article{osti_1227320,
title = {Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes},
author = {Andreev, Konstantin and Bianchi, Christopher and Laursen, Jonas S. and Citterio, Linda and Hein-Kristensen, Line and Gram, Lone and Kuzmenko, Ivan and Olsen, Christian A. and Gidalevitz, David},
abstractNote = {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.},
doi = {10.1016/j.bbamem.2014.05.022},
journal = {Biochimica et Biophysica Acta. Biomembranes},
number = 10,
volume = 1838,
place = {Netherlands},
year = {2014},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1016/j.bbamem.2014.05.022

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Cited by: 18 works
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Works referenced in this record:

Interaction of Gramicidin Derivatives with Phospholipid Monolayers
journal, October 2004

  • Whitehouse, C.; Gidalevitz, D.; Cahuzac, M.
  • Langmuir, Vol. 20, Issue 21
  • DOI: 10.1021/la048797l

Two-Dimensional Crystallography of Amphiphilic Molecules at the Air–Water Interface
journal, February 1992

  • Jacquemain, Didier; Wolf, Sharon Grayer; Leveiller, Franck
  • Angewandte Chemie International Edition in English, Vol. 31, Issue 2
  • DOI: 10.1002/anie.199201301

Biological activities of guanidine compounds
journal, September 2009

  • Saczewski, Franciszek; Balewski, Łukasz
  • Expert Opinion on Therapeutic Patents, Vol. 19, Issue 10
  • DOI: 10.1517/13543770903216675

Protegrin interaction with lipid monolayers: grazing incidence X-ray diffraction and X-ray reflectivity study
journal, January 2008

  • Neville, Frances; Ishitsuka, Yuji; Hodges, Chris S.
  • Soft Matter, Vol. 4, Issue 8
  • DOI: 10.1039/b718295c

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides
journal, February 2008

  • Chongsiriwatana, N. P.; Patch, J. A.; Czyzewski, A. M.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 8
  • DOI: 10.1073/pnas.0708254105

Antimicrobial peptides of multicellular organisms
journal, January 2002


A novel 4-aminobenzyl ester-based carboxy-protecting group for synthesis of atypical peptides by Fmoc-But solid-phase chemistry
journal, January 1995

  • Chan, Weng C.; Bycroft, Barrie W.; Evans, David J.
  • Journal of the Chemical Society, Chemical Communications, Issue 21
  • DOI: 10.1039/c39950002209

Interaction of the Cyclic Antimicrobial Cationic Peptide Bactenecin with the Outer and Cytoplasmic Membrane
journal, January 1999

  • Wu, Manhong; Hancock, Robert E. W.
  • Journal of Biological Chemistry, Vol. 274, Issue 1
  • DOI: 10.1074/jbc.274.1.29

Design of Gram-Negative Selective Antimicrobial Peptides
journal, April 2001

  • Muhle, Steven A.; Tam, James P.
  • Biochemistry, Vol. 40, Issue 19
  • DOI: 10.1021/bi0100384

Urethane protected derivatives of 1-guanylpyrazole for the mild and efficient preparation of guanidines
journal, May 1993


Proteolytic studies of homologous peptide and N-substituted glycine peptoid oligomers
journal, November 1994


Improved antimicrobial peptides based on acyl-lysine oligomers
journal, May 2007

  • Radzishevsky, Inna S.; Rotem, Shahar; Bourdetsky, Dmitry
  • Nature Biotechnology, Vol. 25, Issue 6
  • DOI: 10.1038/nbt1309

Amazing Stability of the Arginine−Phosphate Electrostatic Interaction
journal, August 2005

  • Woods, Amina S.; Ferré, Sergi
  • Journal of Proteome Research, Vol. 4, Issue 4
  • DOI: 10.1021/pr050077s

Interaction of antimicrobial peptide protegrin with biomembranes
journal, May 2003

  • Gidalevitz, D.; Ishitsuka, Y.; Muresan, A. S.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 11
  • DOI: 10.1073/pnas.0934731100

A miniature mimic of host defense peptides with systemic antibacterial efficacy
journal, January 2010

  • Sarig, Hadar; Livne, Liran; Held‐Kuznetsov, Victoria
  • The FASEB Journal, Vol. 24, Issue 6
  • DOI: 10.1096/fj.09-149427

Lipid Headgroup Discrimination by Antimicrobial Peptide LL-37: Insight into Mechanism of Action
journal, February 2006


Surface Studies of Solids by Total Reflection of X-Rays
journal, July 1954


Cholesterol-Phospholipid Interactions: New Insights from Surface X-Ray Scattering Data
journal, March 2010


Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity.
journal, August 1997

  • Steinberg, D. A.; Hurst, M. A.; Fujii, C. A.
  • Antimicrobial Agents and Chemotherapy, Vol. 41, Issue 8
  • DOI: 10.1128/AAC.41.8.1738

Role of the Conformational Rigidity in the Design of Biomimetic Antimicrobial Compounds
journal, September 2010

  • Ivankin, Andrey; Livne, Liran; Mor, Amram
  • Angewandte Chemie International Edition, Vol. 49, Issue 45
  • DOI: 10.1002/anie.201003104

Ion pair formation of phosphorylated amino acids and lysine and arginine side chains: A theoretical study
journal, April 1996


Antibacterial agents based on the cyclic d,l-α-peptide architecture
journal, July 2001

  • Fernandez-Lopez, Sara; Kim, Hui-Sun; Choi, Ellen C.
  • Nature, Vol. 412, Issue 6845
  • DOI: 10.1038/35086601

Recognition of transmembrane helices by the endoplasmic reticulum translocon
journal, January 2005

  • Hessa, Tara; Kim, Hyun; Bihlmaier, Karl
  • Nature, Vol. 433, Issue 7024
  • DOI: 10.1038/nature03216

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers
journal, April 2009

  • Choi, Sungwook; Isaacs, Andre; Clements, Dylan
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 17
  • DOI: 10.1073/pnas.0811818106

Principles and applications of grazing incidence X-ray and neutron scattering from ordered molecular monolayers at the air-water interface
journal, October 1994


Antibacterial activity of bactenecin 5 fragments and their interaction with phospholipid membranes
journal, January 2001

  • Tokunaga, Yoko; Niidome, Takuro; Hatakeyama, Tomomitsu
  • Journal of Peptide Science, Vol. 7, Issue 6
  • DOI: 10.1002/psc.317

α-Peptide/β-Peptoid Chimeras
journal, April 2007

  • Olsen, Christian A.; Bonke, Gitte; Vedel, Line
  • Organic Letters, Vol. 9, Issue 8
  • DOI: 10.1021/ol070316c

Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies
journal, December 2006

  • Hancock, Robert E. W.; Sahl, Hans-Georg
  • Nature Biotechnology, Vol. 24, Issue 12
  • DOI: 10.1038/nbt1267

Antimicrobial peptides stage a comeback
journal, May 2013


Mode of action of linear amphipathic α-helical antimicrobial peptides
journal, January 1998


Analysis of neutron and X-ray reflectivity data by constrained least-squares methods
journal, April 1994


Characterization of Novel Antimicrobial Peptoids
journal, June 1999

  • Goodson, Bob; Ehrhardt, Anton; Ng, Simon
  • Antimicrobial Agents and Chemotherapy, Vol. 43, Issue 6
  • DOI: 10.1128/AAC.43.6.1429

Transformation of an antimicrobial peptide into a plasma membrane-permeable, mitochondria-targeted peptide via the substitution of lysine with arginine
journal, January 2012

  • Nakase, Ikuhiko; Okumura, Shinya; Katayama, Sayaka
  • Chemical Communications, Vol. 48, Issue 90
  • DOI: 10.1039/c2cc35872g

Guanidylation and Tail Effects in Cationic Antimicrobial Lipopeptoids
journal, July 2012


De Novo Design of Antibacterial β-Peptides
journal, December 1999

  • Hamuro, Yoshi; Schneider, Joel P.; DeGrado, William F.
  • Journal of the American Chemical Society, Vol. 121, Issue 51
  • DOI: 10.1021/ja992728p

Full Orthogonality between Dde and Fmoc:  The Direct Synthesis of PNA−Peptide Conjugates
journal, April 2004

  • Díaz-Mochón, Juan Jose; Bialy, Laurent; Bradley, Mark
  • Organic Letters, Vol. 6, Issue 7
  • DOI: 10.1021/ol049905y

Selective cytotoxicity following Arg-to-Lys substitution in tritrpticin adopting a unique amphipathic turn structure
journal, April 2003


Helical Peptoid Mimics of Magainin-2 Amide
journal, October 2003

  • Patch, James A.; Barron, Annelise E.
  • Journal of the American Chemical Society, Vol. 125, Issue 40
  • DOI: 10.1021/ja037320d

Synthesis and antimicrobial activity of dermaseptin S1 analogues
journal, September 2008

  • Savoia, Dianella; Guerrini, Remo; Marzola, Erika
  • Bioorganic & Medicinal Chemistry, Vol. 16, Issue 17
  • DOI: 10.1016/j.bmc.2008.07.032

Roles of Arginine and Lysine Residues in the Translocation of a Cell-Penetrating Peptide from 13 C, 31 P, and 19 F Solid-State NMR
journal, June 2009

  • Su, Yongchao; Doherty, Tim; Waring, Alan J.
  • Biochemistry, Vol. 48, Issue 21
  • DOI: 10.1021/bi900080d

Plectasin, a Fungal Defensin, Targets the Bacterial Cell Wall Precursor Lipid II
journal, May 2010


Characterization and Pathogenic Significance of Vibrio vulnificus Antigens Preferentially Expressed in Septicemic Patients
journal, September 2003


Investigating the cationic side chains of the antimicrobial peptide tritrpticin: Hydrogen bonding properties govern its membrane-disruptive activities
journal, September 2011

  • Nguyen, Leonard T.; de Boer, Leonie; Zaat, Sebastian A. J.
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1808, Issue 9
  • DOI: 10.1016/j.bbamem.2011.05.015

A comparative study on the interactions of SMAP-29 with lipid monolayers
journal, May 2010

  • Neville, Frances; Ivankin, Andrey; Konovalov, Oleg
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1798, Issue 5
  • DOI: 10.1016/j.bbamem.2009.09.017

Mimicry of Antimicrobial Host-Defense Peptides by Random Copolymers
journal, December 2007

  • Mowery, Brendan P.; Lee, Sarah E.; Kissounko, Denis A.
  • Journal of the American Chemical Society, Vol. 129, Issue 50
  • DOI: 10.1021/ja077288d

Biodegradable nanostructures with selective lysis of microbial membranes
journal, April 2011

  • Nederberg, Fredrik; Zhang, Ying; Tan, Jeremy P. K.
  • Nature Chemistry, Vol. 3, Issue 5
  • DOI: 10.1038/nchem.1012

Use of the Cell Wall Precursor Lipid II by a Pore-Forming Peptide Antibiotic
journal, December 1999


Electropositive Charge in α-Defensin Bactericidal Activity: Functional Effects of Lys-for-Arg Substitutions Vary with the Peptide Primary Structure
journal, September 2009

  • Llenado, R. Alan; Weeks, Colby S.; Cocco, Melanie J.
  • Infection and Immunity, Vol. 77, Issue 11
  • DOI: 10.1128/IAI.00695-09

In Vitro Antibacterial Properties of Pexiganan, an Analog of Magainin
journal, April 1999

  • Ge, Yigong; MacDonald, Dorothy L.; Holroyd, Kenneth J.
  • Antimicrobial Agents and Chemotherapy, Vol. 43, Issue 4
  • DOI: 10.1128/AAC.43.4.782

Antimicrobial, Hemolytic, and Cytotoxic Activities of β-Peptoid-Peptide Hybrid Oligomers: Improved Properties Compared to Natural AMPs
journal, May 2010

  • Olsen, Christian A.; Ziegler, Hanne L.; Nielsen, Hanne M.
  • ChemBioChem, Vol. 11, Issue 10
  • DOI: 10.1002/cbic.201000232

Structural models of lipid surface monolayers from X-ray and neutron reflectivity measurements
journal, December 2000


Antiplasmodial and Prehemolytic Activities of α-Peptide–β-Peptoid Chimeras
journal, October 2007


Antibacterial Properties and Mode of Action of a Short Acyl-Lysyl Oligomer
journal, June 2009

  • Zaknoon, Fadia; Sarig, Hadar; Rotem, Shahar
  • Antimicrobial Agents and Chemotherapy, Vol. 53, Issue 8
  • DOI: 10.1128/AAC.00010-09

Host Defence (Cationic) Peptides: What Is Their Future Clinical Potential?
journal, January 1999


Multifunctional cationic host defence peptides and their clinical applications
journal, May 2011

  • Yeung, Amy T. Y.; Gellatly, Shaan L.; Hancock, Robert E. W.
  • Cellular and Molecular Life Sciences, Vol. 68, Issue 13
  • DOI: 10.1007/s00018-011-0710-x

Mechanism of membrane perturbation by the HIV-1 gp41 membrane-proximal external region and its modulation by cholesterol
journal, November 2012

  • Ivankin, Andrey; Apellániz, Beatriz; Gidalevitz, David
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1818, Issue 11
  • DOI: 10.1016/j.bbamem.2012.06.002

Non-haemolytic β-amino-acid oligomers
journal, April 2000

  • Porter, Emilie A.; Wang, Xifang; Lee, Hee-Seung
  • Nature, Vol. 404, Issue 6778
  • DOI: 10.1038/35007145

De novo design of biomimetic antimicrobial polymers
journal, April 2002

  • Tew, G. N.; Liu, D.; Chen, B.
  • Proceedings of the National Academy of Sciences, Vol. 99, Issue 8
  • DOI: 10.1073/pnas.082046199

Stochastic fitting of specular X-ray reflectivity data using StochFit
journal, November 2008

  • Danauskas, Stephen M.; Li, Dongxu; Meron, Mati
  • Journal of Applied Crystallography, Vol. 41, Issue 6
  • DOI: 10.1107/S0021889808032445

Antibacterial cyclic d,l-α-glycopeptides
journal, January 2009

  • Motiei, Leila; Rahimipour, Shai; Thayer, Desiree A.
  • Chemical Communications, Issue 25
  • DOI: 10.1039/b902455g

Synchrotron x-ray diffraction and reflection studies of arachidic acid monolayers at the air-water interface
journal, April 1989

  • Kjaer, K.; Als-Nielsen, J.; Helm, C. A.
  • The Journal of Physical Chemistry, Vol. 93, Issue 8
  • DOI: 10.1021/j100345a063

Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?
journal, March 2005


Some simple ideas on X-ray reflection and grazing-incidence diffraction from thin surfactant films
journal, April 1994


An anti-infective peptide that selectively modulates the innate immune response
journal, March 2007

  • Scott, Monisha G.; Dullaghan, Edie; Mookherjee, Neeloffer
  • Nature Biotechnology, Vol. 25, Issue 4
  • DOI: 10.1038/nbt1288

On the Antimicrobial and Hemolytic Activities of Amphiphilic β-Peptides
journal, October 2001


Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides
journal, August 2005

  • Dartois, Véronique; Sanchez-Quesada, Jorge; Cabezas, Edelmira
  • Antimicrobial Agents and Chemotherapy, Vol. 49, Issue 8
  • DOI: 10.1128/AAC.49.8.3302-3310.2005

Lipid monolayers: why use half a membrane to characterize protein-membrane interactions?
journal, August 1999


CisTrans Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains
journal, February 2013

  • Laursen, Jonas S.; Engel-Andreasen, Jens; Fristrup, Peter
  • Journal of the American Chemical Society, Vol. 135, Issue 7
  • DOI: 10.1021/ja312532x

Designing antimicrobial peptides: form follows function
journal, December 2011

  • Fjell, Christopher D.; Hiss, Jan A.; Hancock, Robert E. W.
  • Nature Reviews Drug Discovery, Vol. 11, Issue 1
  • DOI: 10.1038/nrd3591

Cellular uptake and membrane-destabilising properties of α-peptide/β-peptoid chimeras: lessons for the design of new cell-penetrating peptides
journal, November 2008

  • Foged, Camilla; Franzyk, Henrik; Bahrami, Shervin
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1778, Issue 11
  • DOI: 10.1016/j.bbamem.2008.06.020

Phospholipid and Phospholipid-Protein Monolayers at the Air/Water Interface
journal, October 1990


Mimicking Helical Antibacterial Peptides with Nonpeptidic Folding Oligomers
journal, May 2006


Preface
journal, December 2006