Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance
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
Affiliations
Lisa Bohlmann
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
David M. P. De Oliveira
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Ibrahim M. El-Deeb
Institute for Glycomics, Griffith University, Brisbane, QLD, Australia
Erin B. Brazel
Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
Nichaela Harbison-Price
Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
Cheryl-lynn Y. Ong
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Tania Rivera-Hernandez
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Scott A. Ferguson
Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
Amanda J. Cork
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Minh-Duy Phan
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Amelia T. Soderholm
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Mark R. Davies
Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
Graeme R. Nimmo
Pathology Queensland Central Laboratory, Brisbane, QLD, Australia
Gordon Dougan
Wellcome Trust Sanger Institute, Hinxton, United Kingdom
Mark A. Schembri
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Gregory M. Cook
Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
Alastair G. McEwan
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
Mark von Itzstein
Institute for Glycomics, Griffith University, Brisbane, QLD, Australia
Christopher A. McDevitt
Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
Mark J. Walker
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
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.”
