Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance

ABSTRACT 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....

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Autores principales:	Lisa Bohlmann, David M. P. De Oliveira, Ibrahim M. El-Deeb, Erin B. Brazel, Nichaela Harbison-Price, Cheryl-lynn Y. Ong, Tania Rivera-Hernandez, Scott A. Ferguson, Amanda J. Cork, Minh-Duy Phan, Amelia T. Soderholm, Mark R. Davies, Graeme R. Nimmo, Gordon Dougan, Mark A. Schembri, Gregory M. Cook, Alastair G. McEwan, Mark von Itzstein, Christopher A. McDevitt, Mark J. Walker
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Enterococcus faecium Staphylococcus aureus Streptococcus pyogenes antibiotic resistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/16f22ff0c7c045db9913512c7d5962de
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spelling	oai:doaj.org-article:16f22ff0c7c045db9913512c7d5962de2021-11-15T15:52:19ZChemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance10.1128/mBio.02391-182150-7511https://doaj.org/article/16f22ff0c7c045db9913512c7d5962de2018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02391-18https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus are leading causes of community- and hospital-acquired infection and present a significant clinical challenge. These pathogens have acquired resistance to broad classes of antimicrobials. Furthermore, Streptococcus pyogenes, a significant disease agent among Indigenous Australians, has now acquired resistance to several antibiotic classes. With a rise in antibiotic resistance and reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. As stated by the WHO Director-General, “On current trends, common diseases may become untreatable. Doctors facing patients will have to say, Sorry, there is nothing I can do for you.”Lisa BohlmannDavid M. P. De OliveiraIbrahim M. El-DeebErin B. BrazelNichaela Harbison-PriceCheryl-lynn Y. OngTania Rivera-HernandezScott A. FergusonAmanda J. CorkMinh-Duy PhanAmelia T. SoderholmMark R. DaviesGraeme R. NimmoGordon DouganMark A. SchembriGregory M. CookAlastair G. McEwanMark von ItzsteinChristopher A. McDevittMark J. WalkerAmerican Society for MicrobiologyarticleEnterococcus faeciumStaphylococcus aureusStreptococcus pyogenesantibiotic resistanceMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Enterococcus faecium Staphylococcus aureus Streptococcus pyogenes antibiotic resistance Microbiology QR1-502
spellingShingle	Enterococcus faecium Staphylococcus aureus Streptococcus pyogenes antibiotic resistance Microbiology QR1-502 Lisa Bohlmann David M. P. De Oliveira Ibrahim M. El-Deeb Erin B. Brazel Nichaela Harbison-Price Cheryl-lynn Y. Ong Tania Rivera-Hernandez Scott A. Ferguson Amanda J. Cork Minh-Duy Phan Amelia T. Soderholm Mark R. Davies Graeme R. Nimmo Gordon Dougan Mark A. Schembri Gregory M. Cook Alastair G. McEwan Mark von Itzstein Christopher A. McDevitt Mark J. Walker Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance
description	ABSTRACT 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. IMPORTANCE The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus are leading causes of community- and hospital-acquired infection and present a significant clinical challenge. These pathogens have acquired resistance to broad classes of antimicrobials. Furthermore, Streptococcus pyogenes, a significant disease agent among Indigenous Australians, has now acquired resistance to several antibiotic classes. With a rise in antibiotic resistance and reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. As stated by the WHO Director-General, “On current trends, common diseases may become untreatable. Doctors facing patients will have to say, Sorry, there is nothing I can do for you.”
format	article
author	Lisa Bohlmann David M. P. De Oliveira Ibrahim M. El-Deeb Erin B. Brazel Nichaela Harbison-Price Cheryl-lynn Y. Ong Tania Rivera-Hernandez Scott A. Ferguson Amanda J. Cork Minh-Duy Phan Amelia T. Soderholm Mark R. Davies Graeme R. Nimmo Gordon Dougan Mark A. Schembri Gregory M. Cook Alastair G. McEwan Mark von Itzstein Christopher A. McDevitt Mark J. Walker
author_facet	Lisa Bohlmann David M. P. De Oliveira Ibrahim M. El-Deeb Erin B. Brazel Nichaela Harbison-Price Cheryl-lynn Y. Ong Tania Rivera-Hernandez Scott A. Ferguson Amanda J. Cork Minh-Duy Phan Amelia T. Soderholm Mark R. Davies Graeme R. Nimmo Gordon Dougan Mark A. Schembri Gregory M. Cook Alastair G. McEwan Mark von Itzstein Christopher A. McDevitt Mark J. Walker
author_sort	Lisa Bohlmann
title	Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance
title_short	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_sort	chemical synergy between ionophore pbt2 and zinc reverses antibiotic resistance
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/16f22ff0c7c045db9913512c7d5962de
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Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance

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