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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]
  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 Lab. (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. https://doi.org/10.1371/journal.pone.0222211.
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
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.
@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 = {2019},
month = {9}
}

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