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Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance
The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we r...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299484/ https://www.ncbi.nlm.nih.gov/pubmed/30538186 http://dx.doi.org/10.1128/mBio.02391-18 |
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author | Bohlmann, Lisa De Oliveira, David M. P. El-Deeb, Ibrahim M. Brazel, Erin B. Harbison-Price, Nichaela Ong, Cheryl-lynn Y. Rivera-Hernandez, Tania Ferguson, Scott A. Cork, Amanda J. Phan, Minh-Duy Soderholm, Amelia T. Davies, Mark R. Nimmo, Graeme R. Dougan, Gordon Schembri, Mark A. Cook, Gregory M. McEwan, Alastair G. von Itzstein, Mark McDevitt, Christopher A. Walker, Mark J. |
author_facet | Bohlmann, Lisa De Oliveira, David M. P. El-Deeb, Ibrahim M. Brazel, Erin B. Harbison-Price, Nichaela Ong, Cheryl-lynn Y. Rivera-Hernandez, Tania Ferguson, Scott A. Cork, Amanda J. Phan, Minh-Duy Soderholm, Amelia T. Davies, Mark R. Nimmo, Graeme R. Dougan, Gordon Schembri, Mark A. Cook, Gregory M. McEwan, Alastair G. von Itzstein, Mark McDevitt, Christopher A. Walker, Mark J. |
author_sort | Bohlmann, Lisa |
collection | PubMed |
description | The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we report the synergy between ionophore-induced physiological stress in Gram-positive bacteria and antibiotic treatment. PBT2 is a safe-for-human-use zinc ionophore that has progressed to phase 2 clinical trials for Alzheimer’s and Huntington’s disease treatment. In combination with zinc, PBT2 exhibits antibacterial activity and disrupts cellular homeostasis in erythromycin-resistant group A Streptococcus (GAS), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). We were unable to select for mutants resistant to PBT2-zinc treatment. While ineffective alone against resistant bacteria, several clinically relevant antibiotics act synergistically with PBT2-zinc to enhance killing of these Gram-positive pathogens. These data represent a new paradigm whereby disruption of bacterial metal homeostasis reverses antibiotic-resistant phenotypes in a number of priority human bacterial pathogens. |
format | Online Article Text |
id | pubmed-6299484 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-62994842018-12-28 Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance Bohlmann, Lisa De Oliveira, David M. P. El-Deeb, Ibrahim M. Brazel, Erin B. Harbison-Price, Nichaela Ong, Cheryl-lynn Y. Rivera-Hernandez, Tania Ferguson, Scott A. Cork, Amanda J. Phan, Minh-Duy Soderholm, Amelia T. Davies, Mark R. Nimmo, Graeme R. Dougan, Gordon Schembri, Mark A. Cook, Gregory M. McEwan, Alastair G. von Itzstein, Mark McDevitt, Christopher A. Walker, Mark J. mBio Research Article The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we report the synergy between ionophore-induced physiological stress in Gram-positive bacteria and antibiotic treatment. PBT2 is a safe-for-human-use zinc ionophore that has progressed to phase 2 clinical trials for Alzheimer’s and Huntington’s disease treatment. In combination with zinc, PBT2 exhibits antibacterial activity and disrupts cellular homeostasis in erythromycin-resistant group A Streptococcus (GAS), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). We were unable to select for mutants resistant to PBT2-zinc treatment. While ineffective alone against resistant bacteria, several clinically relevant antibiotics act synergistically with PBT2-zinc to enhance killing of these Gram-positive pathogens. These data represent a new paradigm whereby disruption of bacterial metal homeostasis reverses antibiotic-resistant phenotypes in a number of priority human bacterial pathogens. American Society for Microbiology 2018-12-11 /pmc/articles/PMC6299484/ /pubmed/30538186 http://dx.doi.org/10.1128/mBio.02391-18 Text en Copyright © 2018 Bohlmann et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Bohlmann, Lisa De Oliveira, David M. P. El-Deeb, Ibrahim M. Brazel, Erin B. Harbison-Price, Nichaela Ong, Cheryl-lynn Y. Rivera-Hernandez, Tania Ferguson, Scott A. Cork, Amanda J. Phan, Minh-Duy Soderholm, Amelia T. Davies, Mark R. Nimmo, Graeme R. Dougan, Gordon Schembri, Mark A. Cook, Gregory M. McEwan, Alastair G. von Itzstein, Mark McDevitt, Christopher A. Walker, Mark J. Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance |
title | Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance |
title_full | Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance |
title_fullStr | Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance |
title_full_unstemmed | Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance |
title_short | Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance |
title_sort | chemical synergy between ionophore pbt2 and zinc reverses antibiotic resistance |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299484/ https://www.ncbi.nlm.nih.gov/pubmed/30538186 http://dx.doi.org/10.1128/mBio.02391-18 |
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