Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Scope and efficacy of the broad-spectrum topical antiseptic choline geranate

Abstract

Choline geranate (also described as Choline And GEranic acid, or CAGE) has been developed as a novel biocompatible antiseptic material capable of penetrating skin and aiding the transdermal delivery of co-administered antibiotics. The antibacterial properties of CAGE were analyzed against 24 and 72 hour old biofilms of 11 clinically isolated ESKAPE pathogens (defined as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter sp, respectively), including multidrug resistant (MDR) isolates. CAGE was observed to eradicate in vitro biofilms at concentrations as low as 3.56 mM (0.156% v:v) in as little as 2 hours, which represents both an improved potency and rate of biofilm eradication relative to that reported for most common standard-of-care topical antiseptics in current use. In vitro time-kill studies on 24 hour old Staphylococcus aureus biofilms indicate that CAGE exerts its antibacterial effect upon contact and a 0.1% v:v solution reduced biofilm viability by over three orders of magnitude (a 3log10 reduction) in 15 minutes. Furthermore, disruption of the protective layer of exopolymeric substances in mature biofilms of Staphylococcus aureus by CAGE (0.1% v:v) was observed in 120 minutes. Insight into the mechanism of action of CAGE was provided with molecular modeling studies alongside inmore » vitro antibiofilm assays. The geranate ion and geranic acid components of CAGE are predicted to act in concert to integrate into bacterial membranes, affect membrane thinning and perturb membrane homeostasis. Taken together, our results show that CAGE demonstrates all properties required of an effective topical antiseptic and the data also provides insight into how its observed antibiofilm properties may manifest.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [3];  [1];  [3]; ORCiD logo [1]; ORCiD logo [4];  [2]; ORCiD logo [1]
+ Show Author Affiliations
  1. Northern Arizona Univ., Flagstaff, AZ (United States)
  2. Dixie State Univ., St. George, UT (United States)
  3. The College of New Jersey, Ewing, NJ (United States)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1597369
Report Number(s):
LA-UR-19-31572
Journal ID: ISSN 1932-6203
Grant/Contract Number:  
89233218CNA000001; OAC-1828163; OAC-1826915
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 14; Journal Issue: 9; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science; choline geranate, antiseptic, antibiofilm, ionic liquids, deep eutectic solvent, ESKAPE pathogens

Citation Formats

Greene, Joshua R., Merrett, Kahla L., Heyert, Alexanndra J., Simmons, Lucas F., Migliori, Camille M., Vogt, Kristen C., Castro, Rebeca S., Phillips, Paul D., Baker, Joseph L., Lindberg, Gerrick E., Fox, David T., Del Sesto, Rico E., and Koppisch, Andrew T. Scope and efficacy of the broad-spectrum topical antiseptic choline geranate. United States: N. p., 2019. Web. doi:10.1371/journal.pone.0222211.
Copy to clipboard
Greene, Joshua R., Merrett, Kahla L., Heyert, Alexanndra J., Simmons, Lucas F., Migliori, Camille M., Vogt, Kristen C., Castro, Rebeca S., Phillips, Paul D., Baker, Joseph L., Lindberg, Gerrick E., Fox, David T., Del Sesto, Rico E., & Koppisch, Andrew T. Scope and efficacy of the broad-spectrum topical antiseptic choline geranate. United States. https://doi.org/10.1371/journal.pone.0222211
Copy to clipboard
Greene, Joshua R., Merrett, Kahla L., Heyert, Alexanndra J., Simmons, Lucas F., Migliori, Camille M., Vogt, Kristen C., Castro, Rebeca S., Phillips, Paul D., Baker, Joseph L., Lindberg, Gerrick E., Fox, David T., Del Sesto, Rico E., and Koppisch, Andrew T. Tue . "Scope and efficacy of the broad-spectrum topical antiseptic choline geranate". United States. https://doi.org/10.1371/journal.pone.0222211. https://www.osti.gov/servlets/purl/1597369.
Copy to clipboard
@article{osti_1597369,
title = {Scope and efficacy of the broad-spectrum topical antiseptic choline geranate},
author = {Greene, Joshua R. and Merrett, Kahla L. and Heyert, Alexanndra J. and Simmons, Lucas F. and Migliori, Camille M. and Vogt, Kristen C. and Castro, Rebeca S. and Phillips, Paul D. and Baker, Joseph L. and Lindberg, Gerrick E. and Fox, David T. and Del Sesto, Rico E. and Koppisch, Andrew T.},
abstractNote = {Choline geranate (also described as Choline And GEranic acid, or CAGE) has been developed as a novel biocompatible antiseptic material capable of penetrating skin and aiding the transdermal delivery of co-administered antibiotics. The antibacterial properties of CAGE were analyzed against 24 and 72 hour old biofilms of 11 clinically isolated ESKAPE pathogens (defined as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter sp, respectively), including multidrug resistant (MDR) isolates. CAGE was observed to eradicate in vitro biofilms at concentrations as low as 3.56 mM (0.156% v:v) in as little as 2 hours, which represents both an improved potency and rate of biofilm eradication relative to that reported for most common standard-of-care topical antiseptics in current use. In vitro time-kill studies on 24 hour old Staphylococcus aureus biofilms indicate that CAGE exerts its antibacterial effect upon contact and a 0.1% v:v solution reduced biofilm viability by over three orders of magnitude (a 3log10 reduction) in 15 minutes. Furthermore, disruption of the protective layer of exopolymeric substances in mature biofilms of Staphylococcus aureus by CAGE (0.1% v:v) was observed in 120 minutes. Insight into the mechanism of action of CAGE was provided with molecular modeling studies alongside in vitro antibiofilm assays. The geranate ion and geranic acid components of CAGE are predicted to act in concert to integrate into bacterial membranes, affect membrane thinning and perturb membrane homeostasis. Taken together, our results show that CAGE demonstrates all properties required of an effective topical antiseptic and the data also provides insight into how its observed antibiofilm properties may manifest.},
doi = {10.1371/journal.pone.0222211},
journal = {PLoS ONE},
number = 9,
volume = 14,
place = {United States},
year = {Tue Sep 17 00:00:00 EDT 2019},
month = {Tue Sep 17 00:00:00 EDT 2019}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1371/journal.pone.0222211
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 11 works
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Ionic liquids as a class of materials for transdermal delivery and pathogen neutralization
journal, August 2014

  • Zakrewsky, Michael; Lovejoy, Katherine S.; Kern, Theresa L.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 37
  • DOI: 10.1073/pnas.1403995111

An auto-inducible mechanism for ionic liquid resistance in microbial biofuel production
journal, March 2014

  • Ruegg, Thomas L.; Kim, Eun-Mi; Simmons, Blake A.
  • Nature Communications, Vol. 5, Issue 1
  • DOI: 10.1038/ncomms4490

From in vitro to in vivo Models of Bacterial Biofilm-Related Infections
journal, May 2013

Membrane Thinning and Thickening Induced by Membrane-Active Amphipathic Peptides
journal, June 2016

  • Grage, Stephan L.; Afonin, Sergii; Kara, Sezgin
  • Frontiers in Cell and Developmental Biology, Vol. 4
  • DOI: 10.3389/fcell.2016.00065

Ionic liquids for oral insulin delivery
journal, June 2018

  • Banerjee, Amrita; Ibsen, Kelly; Brown, Tyler
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 28
  • DOI: 10.1073/pnas.1722338115

Membrane thinning caused by magainin 2
journal, December 1995

Antimicrobial and antibiofilm activities of 1-alkylquinolinium bromide ionic liquids
journal, January 2010

  • Busetti, Alessandro; Crawford, Deborah E.; Earle, Martyn J.
  • Green Chemistry, Vol. 12, Issue 3
  • DOI: 10.1039/b919872e

The antimicrobial potential of ionic liquids: A source of chemical diversity for infection and biofilm control
journal, August 2015

Reply to Rogers and Gurau: Definitions of ionic liquids and deep eutectic solvents
journal, November 2018

  • Banerjee, Amrita; Ibsen, Kelly; Brown, Tyler
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 47
  • DOI: 10.1073/pnas.1815526115

Describing the Mechanism of Antimicrobial Peptide Action with the Interfacial Activity Model
journal, August 2010

Antibiofilm activities of 1-alkyl-3-methylimidazolium chloride ionic liquids
journal, January 2009

  • Carson, Louise; Chau, Peter K. W.; Earle, Martyn J.
  • Green Chemistry, Vol. 11, Issue 4
  • DOI: 10.1039/b821842k

Riddle of Biofilm Resistance
journal, April 2001

Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms
journal, April 2002

Transdermal insulin delivery using choline-based ionic liquids (CAGE)
journal, September 2018

Role of Antibiotic Penetration Limitation in Klebsiella pneumoniae Biofilm Resistance to Ampicillin and Ciprofloxacin
journal, July 2000

Efficacy of Dilute Povidone-Iodine against Multi- Drug Resistant Bacterial Biofilms, Fungal Biofilms and Fungal Spores
journal, January 2018

Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent
journal, March 2017

  • Banerjee, Amrita; Ibsen, Kelly; Iwao, Yasunori
  • Advanced Healthcare Materials, Vol. 6, Issue 15
  • DOI: 10.1002/adhm.201601411

Manuka honey treatment of biofilms of Pseudomonas aeruginosa results in the emergence of isolates with increased honey resistance
journal, January 2014

  • Camplin, Aimee L.; Maddocks, Sarah E.
  • Annals of Clinical Microbiology and Antimicrobials, Vol. 13, Issue 1
  • DOI: 10.1186/1476-0711-13-19

Choline and Geranate Deep Eutectic Solvent as a Broad-Spectrum Antiseptic Agent for Preventive and Therapeutic Applications
journal, March 2016

  • Zakrewsky, Michael; Banerjee, Amrita; Apte, Sanjana
  • Advanced Healthcare Materials, Vol. 5, Issue 11
  • DOI: 10.1002/adhm.201600086

Molecular Basis of In Vivo Biofilm Formation by Bacterial Pathogens
journal, December 2012

Antibiotic resistance of bacteria in biofilms
journal, July 2001

Bacterial Biofilms: A Common Cause of Persistent Infections
journal, May 1999

Is “choline and geranate” an ionic liquid or deep eutectic solvent system?
journal, November 2018

  • Rogers, Robin D.; Gurau, Gabriela
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 47
  • DOI: 10.1073/pnas.1814976115

Comparison of simple potential functions for simulating liquid water
journal, July 1983

  • Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
  • The Journal of Chemical Physics, Vol. 79, Issue 2
  • DOI: 10.1063/1.445869

Understanding biofilm resistance to antibacterial agents
journal, February 2003

  • Davies, David
  • Nature Reviews Drug Discovery, Vol. 2, Issue 2
  • DOI: 10.1038/nrd1008

Antimicrobial peptides: New candidates in the fight against bacterial infections
journal, January 2005

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms
journal, May 2017

  • Solinski, Amy E.; Koval, Alexander B.; Brzozowski, Richard S.
  • Journal of the American Chemical Society, Vol. 139, Issue 21
  • DOI: 10.1021/jacs.7b03879

Development of a Native Escherichia coli Induction System for Ionic Liquid Tolerance
journal, July 2014

In vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria
journal, October 2011

  • Leid, J. G.; Ditto, A. J.; Knapp, A.
  • Journal of Antimicrobial Chemotherapy, Vol. 67, Issue 1
  • DOI: 10.1093/jac/dkr408

PACKMOL: A package for building initial configurations for molecular dynamics simulations
journal, October 2009

  • Martínez, L.; Andrade, R.; Birgin, E. G.
  • Journal of Computational Chemistry, Vol. 30, Issue 13
  • DOI: 10.1002/jcc.21224

Lipid14: The Amber Lipid Force Field
journal, January 2014

  • Dickson, Callum J.; Madej, Benjamin D.; Skjevik, Åge A.
  • Journal of Chemical Theory and Computation, Vol. 10, Issue 2
  • DOI: 10.1021/ct4010307

Mechanism of Antibacterial Activity of Choline-Based Ionic Liquids (CAGE)
journal, April 2018

Utilization of Metal Halide Species Ambiguity to Develop Amorphous, Stabilized Pharmaceutical Agents As Ionic Liquids
journal, October 2012

  • Lovejoy, Katherine S.; Corley, Cynthia A.; Cope, Emily K.
  • Crystal Growth & Design, Vol. 12, Issue 11
  • DOI: 10.1021/cg300969u

Development and testing of a general amber force field
journal, January 2004

  • Wang, Junmei; Wolf, Romain M.; Caldwell, James W.
  • Journal of Computational Chemistry, Vol. 25, Issue 9
  • DOI: 10.1002/jcc.20035

Cationic antiseptics: diversity of action under a common epithet
journal, October 2005

Molecular mechanism of antimicrobial peptides: The origin of cooperativity
journal, September 2006

The impact of peptides on lipid membranes
journal, July 2008

  • Khandelia, Himanshu; Ipsen, John H.; Mouritsen, Ole G.
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1778, Issue 7-8
  • DOI: 10.1016/j.bbamem.2008.02.009

Single-Pot Extraction-Analysis of Dyed Wool Fibers with Ionic Liquids
journal, September 2012

  • Lovejoy, Katherine S.; Lou, Alexander J.; Davis, Lauren E.
  • Analytical Chemistry, Vol. 84, Issue 21
  • DOI: 10.1021/ac301873s

Tetraalkylphosphonium-Based Ionic Liquids for a Single-Step Dye Extraction/MALDI MS Analysis Platform
journal, April 2011

  • Lovejoy, Katherine S.; Purdy, Geraldine M.; Iyer, Srinivas
  • Analytical Chemistry, Vol. 83, Issue 8
  • DOI: 10.1021/ac102944w

Evaluation of short exposure times of antimicrobial wound solutions against microbial biofilms: from in vitro to in vivo
journal, November 2017

  • Johani, K.; Malone, M.; Jensen, S. O.
  • Journal of Antimicrobial Chemotherapy, Vol. 73, Issue 2
  • DOI: 10.1093/jac/dkx391

Clinical relevance of the ESKAPE pathogens
journal, March 2013

  • Pendleton, Jack N.; Gorman, Sean P.; Gilmore, Brendan F.
  • Expert Review of Anti-infective Therapy, Vol. 11, Issue 3
  • DOI: 10.1586/eri.13.12

Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy
journal, October 2012

Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms
journal, June 2002

  • Pugliese, Gina; Favero, Martin S.
  • Infection Control & Hospital Epidemiology, Vol. 23, Issue 6
  • DOI: 10.1017/s0195941700082850

NADPH levels affect cellular epigenetic state by inhibiting HDAC3–Ncor complex
journal, January 2021

Membrane Thinning and Thickening Induced by Membrane-Active Amphipathic Peptides
text, January 2016

Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent
journal, March 2017

  • Banerjee, Amrita; Ibsen, Kelly; Iwao, Yasunori
  • Advanced Healthcare Materials, Vol. 6, Issue 15
  • DOI: 10.1002/adhm.201601411

PACKMOL: A package for building initial configurations for molecular dynamics simulations
journal, October 2009

  • Martínez, L.; Andrade, R.; Birgin, E. G.
  • Journal of Computational Chemistry, Vol. 30, Issue 13
  • DOI: 10.1002/jcc.21224

Visualization and characterization of Enterococcus faecalis biofilm structure in bovine dentin using 2D and 3D microscopic techniques
journal, September 2020

The impact of peptides on lipid membranes
journal, July 2008

  • Khandelia, Himanshu; Ipsen, John H.; Mouritsen, Ole G.
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1778, Issue 7-8
  • DOI: 10.1016/j.bbamem.2008.02.009

Transdermal insulin delivery using choline-based ionic liquids (CAGE)
journal, September 2018

Single-Pot Extraction-Analysis of Dyed Wool Fibers with Ionic Liquids
journal, September 2012

  • Lovejoy, Katherine S.; Lou, Alexander J.; Davis, Lauren E.
  • Analytical Chemistry, Vol. 84, Issue 21
  • DOI: 10.1021/ac301873s

Membrane thinning caused by magainin 2
journal, December 1995

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms
journal, May 2017

  • Solinski, Amy E.; Koval, Alexander B.; Brzozowski, Richard S.
  • Journal of the American Chemical Society, Vol. 139, Issue 21
  • DOI: 10.1021/jacs.7b03879

An auto-inducible mechanism for ionic liquid resistance in microbial biofuel production
journal, March 2014

  • Ruegg, Thomas L.; Kim, Eun-Mi; Simmons, Blake A.
  • Nature Communications, Vol. 5, Issue 1
  • DOI: 10.1038/ncomms4490

Understanding biofilm resistance to antibacterial agents
journal, February 2003

  • Davies, David
  • Nature Reviews Drug Discovery, Vol. 2, Issue 2
  • DOI: 10.1038/nrd1008

Antibiofilm activities of 1-alkyl-3-methylimidazolium chloride ionic liquids
journal, January 2009

  • Carson, Louise; Chau, Peter K. W.; Earle, Martyn J.
  • Green Chemistry, Vol. 11, Issue 4
  • DOI: 10.1039/b821842k

All-atom lipid bilayer self-assembly with the AMBER and CHARMM lipid force fields
journal, January 2015

  • Skjevik, Åge A.; Madej, Benjamin D.; Dickson, Callum J.
  • Chemical Communications, Vol. 51, Issue 21
  • DOI: 10.1039/c4cc09584g

Comparison of simple potential functions for simulating liquid water
journal, July 1983

  • Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
  • The Journal of Chemical Physics, Vol. 79, Issue 2
  • DOI: 10.1063/1.445869

Ionic liquids for oral insulin delivery
journal, June 2018

  • Banerjee, Amrita; Ibsen, Kelly; Brown, Tyler
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 28
  • DOI: 10.1073/pnas.1722338115

Is “choline and geranate” an ionic liquid or deep eutectic solvent system?
journal, November 2018

  • Rogers, Robin D.; Gurau, Gabriela
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 47
  • DOI: 10.1073/pnas.1814976115

Reply to Rogers and Gurau: Definitions of ionic liquids and deep eutectic solvents
journal, November 2018

  • Banerjee, Amrita; Ibsen, Kelly; Brown, Tyler
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 47
  • DOI: 10.1073/pnas.1815526115

In vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria
journal, October 2011

  • Leid, J. G.; Ditto, A. J.; Knapp, A.
  • Journal of Antimicrobial Chemotherapy, Vol. 67, Issue 1
  • DOI: 10.1093/jac/dkr408

The extracellular matrix protectsPseudomonas aeruginosabiofilms by limiting the penetration of tobramycin
journal, June 2013

Bacterial Biofilms: A Common Cause of Persistent Infections
journal, May 1999

Impact of Multidrug-Resistant Pseudomonas aeruginosa Bacteremia on Patient Outcomes
journal, June 2010

  • Tam, V. H.; Rogers, C. A.; Chang, K. -T.
  • Antimicrobial Agents and Chemotherapy, Vol. 54, Issue 9
  • DOI: 10.1128/aac.00207-10

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics
journal, September 2014

  • Lebeaux, D.; Ghigo, J. -M.; Beloin, C.
  • Microbiology and Molecular Biology Reviews, Vol. 78, Issue 3
  • DOI: 10.1128/mmbr.00013-14

Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy
journal, October 2012

Development of a Native Escherichia coli Induction System for Ionic Liquid Tolerance
journal, July 2014

Antibiotic lock therapy: review of technique and logistical challenges
journal, December 2014

  • Bookstaver, Brandon; Justo, Julie Ann
  • Infection and Drug Resistance
  • DOI: 10.2147/idr.s51388

From in vitro to in vivo Models of Bacterial Biofilm-Related Infections
journal, May 2013

Introducing Parsl: A Python Parallel Scripting Library
text, January 2017

Membrane Thinning and Thickening Induced by Membrane-Active Amphipathic Peptides
text, January 2016

    Sort by:
    [ × clear filter / sort ]

    Similar Records in DOE PAGES and OSTI.GOV collections: