Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/117821
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | Chemical synergy between ionophore PBT2 and zinc reverses antibiotic resistance |
Author: | Bohlmann, L. De Oliveira, D.M.P. El-Deeb, I.M. Brazel, E.B. Harbison-Price, N. Ong, C.L.Y. Rivera-Hernandez, T. Ferguson, S.A. Cork, A.J. Phan, M.D. Soderholm, A.T. Davies, M.R. Nimmo, G.R. Dougan, G. Schembri, M.A. Cook, G.M. McEwan, A.G. von Itzstein, M. McDevitt, C.A. Walker, M.J. |
Citation: | mBio, 2018; 9(6):e02391-18-1-e02391-18-12 |
Publisher: | American Academy of Microbiology |
Issue Date: | 2018 |
ISSN: | 2161-2129 2150-7511 |
Editor: | Kline, K.A. |
Statement of Responsibility: | Lisa Bohlmann, David M. P. De Oliveira, Ibrahim M. El-Deeb, Erin B. Brazel, Nichaela Harbison-Price |
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." |
Keywords: | Enterococcus faecium Staphylococcus aureus Streptococcus pyogenes antibiotic resistance |
Rights: | © 2018 Bohlmann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
DOI: | 10.1128/mBio.02391-18 |
Grant ID: | ARC |
Published version: | http://dx.doi.org/10.1128/mbio.02391-18 |
Appears in Collections: | Aurora harvest 8 Microbiology and Immunology publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
hdl_117821.pdf | Published version | 2.3 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.