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NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131

BACKGROUND AND PURPOSE: Treatment of infections caused by NDM-1 carbapenemase-producing Enterobacteriaceae (CPE) represents one of the major challenges of modern medicine. In order to address this issue, we tested ceragenins (CSAs – cationic steroid antimicrobials) as promising agents to eradicate v...

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Autores principales: Chmielewska, Sylwia Joanna, Skłodowski, Karol, Piktel, Ewelina, Suprewicz, Łukasz, Fiedoruk, Krzysztof, Daniluk, Tamara, Wolak, Przemysław, Savage, Paul B, Bucki, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535143/
https://www.ncbi.nlm.nih.gov/pubmed/33061475
http://dx.doi.org/10.2147/IDR.S261579
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author Chmielewska, Sylwia Joanna
Skłodowski, Karol
Piktel, Ewelina
Suprewicz, Łukasz
Fiedoruk, Krzysztof
Daniluk, Tamara
Wolak, Przemysław
Savage, Paul B
Bucki, Robert
author_facet Chmielewska, Sylwia Joanna
Skłodowski, Karol
Piktel, Ewelina
Suprewicz, Łukasz
Fiedoruk, Krzysztof
Daniluk, Tamara
Wolak, Przemysław
Savage, Paul B
Bucki, Robert
author_sort Chmielewska, Sylwia Joanna
collection PubMed
description BACKGROUND AND PURPOSE: Treatment of infections caused by NDM-1 carbapenemase-producing Enterobacteriaceae (CPE) represents one of the major challenges of modern medicine. In order to address this issue, we tested ceragenins (CSAs – cationic steroid antimicrobials) as promising agents to eradicate various NDM-1-producing Gram-negative enteric rods. MATERIALS AND METHODS: Susceptibility to CSA-13, CSA-44, and CSA-131 of four reference NDM-1 carbapenemase-producing strains, ie, Escherichia coli BAA-2471, Enterobacter cloacae BAA-2468, Klebsiella pneumoniae subsp. pneumoniae BAA-2472, and K. pneumoniae BAA-2473 was assessed by MIC/MBC testing of planktonic cells as well as biofilm formation/disruption assays. To define the mechanism of CSAs bactericidal activity, their ability to induce generation of reactive oxygen species (ROS), permeabilization of the inner and outer membranes, and their mechanical and adhesive properties upon CSA addition were examined. Additionally, hemolytic assays were performed to assess CSAs hemocompatibility. RESULTS: All tested CSAs exert substantial bactericidal activity against NDM-1-producing bacteria. Moreover, CSAs significantly prevent biofilm formation as well as reduce the mass of developed biofilms. The mechanism of CSA action comprises both increased permeability of the outer and inner membrane, which is associated with an extensive ROS generation. Additionally, atomic force microscopy (AFM) analysis has shown morphological alterations in bacterial cells and the reduction of stiffness and adhesion properties. Importantly, CSAs are characterized by low hemolytic activity at concentrations that are bactericidal. CONCLUSION: Development of ceragenins should be viewed as one of the valid strategies to provide new treatment options against infections associated with CPE. The studies presented herein demonstrate that NDM-1-positive bacteria are more susceptible to ceragenins than to conventional antibiotics. In effect, CSA-13, CSA-44, and CSA-131 may be favorable for prevention and decrease of global burden of CPE.
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spelling pubmed-75351432020-10-14 NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131 Chmielewska, Sylwia Joanna Skłodowski, Karol Piktel, Ewelina Suprewicz, Łukasz Fiedoruk, Krzysztof Daniluk, Tamara Wolak, Przemysław Savage, Paul B Bucki, Robert Infect Drug Resist Original Research BACKGROUND AND PURPOSE: Treatment of infections caused by NDM-1 carbapenemase-producing Enterobacteriaceae (CPE) represents one of the major challenges of modern medicine. In order to address this issue, we tested ceragenins (CSAs – cationic steroid antimicrobials) as promising agents to eradicate various NDM-1-producing Gram-negative enteric rods. MATERIALS AND METHODS: Susceptibility to CSA-13, CSA-44, and CSA-131 of four reference NDM-1 carbapenemase-producing strains, ie, Escherichia coli BAA-2471, Enterobacter cloacae BAA-2468, Klebsiella pneumoniae subsp. pneumoniae BAA-2472, and K. pneumoniae BAA-2473 was assessed by MIC/MBC testing of planktonic cells as well as biofilm formation/disruption assays. To define the mechanism of CSAs bactericidal activity, their ability to induce generation of reactive oxygen species (ROS), permeabilization of the inner and outer membranes, and their mechanical and adhesive properties upon CSA addition were examined. Additionally, hemolytic assays were performed to assess CSAs hemocompatibility. RESULTS: All tested CSAs exert substantial bactericidal activity against NDM-1-producing bacteria. Moreover, CSAs significantly prevent biofilm formation as well as reduce the mass of developed biofilms. The mechanism of CSA action comprises both increased permeability of the outer and inner membrane, which is associated with an extensive ROS generation. Additionally, atomic force microscopy (AFM) analysis has shown morphological alterations in bacterial cells and the reduction of stiffness and adhesion properties. Importantly, CSAs are characterized by low hemolytic activity at concentrations that are bactericidal. CONCLUSION: Development of ceragenins should be viewed as one of the valid strategies to provide new treatment options against infections associated with CPE. The studies presented herein demonstrate that NDM-1-positive bacteria are more susceptible to ceragenins than to conventional antibiotics. In effect, CSA-13, CSA-44, and CSA-131 may be favorable for prevention and decrease of global burden of CPE. Dove 2020-09-28 /pmc/articles/PMC7535143/ /pubmed/33061475 http://dx.doi.org/10.2147/IDR.S261579 Text en © 2020 Chmielewska et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Chmielewska, Sylwia Joanna
Skłodowski, Karol
Piktel, Ewelina
Suprewicz, Łukasz
Fiedoruk, Krzysztof
Daniluk, Tamara
Wolak, Przemysław
Savage, Paul B
Bucki, Robert
NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131
title NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131
title_full NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131
title_fullStr NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131
title_full_unstemmed NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131
title_short NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131
title_sort ndm-1 carbapenemase-producing enterobacteriaceae are highly susceptible to ceragenins csa-13, csa-44, and csa-131
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535143/
https://www.ncbi.nlm.nih.gov/pubmed/33061475
http://dx.doi.org/10.2147/IDR.S261579
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