Learning, I think you could find some answers in the papers by Lisa Bohlmann, who was the first author in the paper where they found PBT2 to kill treatment-resistant bacteria. Viruses are different than bacteria, however. Here I repost the last paper:Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
AffiliationsAffiliations
- 1 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
- 2 School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
- 3 Institute for Glycomics, Griffith University, Queensland, Australia.
- 4 School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, Australia.
- 5 Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
- 6 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand [email protected].
- PMID: 32188750
- DOI: 10.1128/mSphere.00157-20
Item in ClipboardMultiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
Nichaela Harbison-Price et al. mSphere. 2020Authors
Affiliations
- 1 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
- 2 School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
- 3 Institute for Glycomics, Griffith University, Queensland, Australia.
- 4 School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre, The University of Queensland, Queensland, Australia.
- 5 Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
- 6 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand [email protected].
- PMID: 32188750
- DOI: 10.1128/mSphere.00157-20
Item in ClipboardAbstract
Globally, more antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance (AMR). The development of novel ionophores, a class of antimicrobials used exclusively in animals, holds promise as a strategy to replace or reduce essential human antimicrobials in veterinary practice. PBT2 is a zinc ionophore with recently demonstrated antibacterial activity against several Gram-positive pathogens, although the underlying mechanism of action is unknown. Here, we investigated the bactericidal mechanism of PBT2 in the bovine mastitis-causing pathogen, Streptococcus uberis In this work, we show that PBT2 functions as a Zn2+/H+ ionophore, exchanging extracellular zinc for intracellular protons in an electroneutral process that leads to cellular zinc accumulation. Zinc accumulation occurs concomitantly with manganese depletion and the production of reactive oxygen species (ROS). PBT2 inhibits the activity of the manganese-dependent superoxide dismutase, SodA, thereby impairing oxidative stress protection. We propose that PBT2-mediated intracellular zinc toxicity in S. uberis leads to lethality through multiple bactericidal mechanisms: the production of toxic ROS and the impairment of manganese-dependent antioxidant functions. Collectively, these data show that PBT2 represents a new class of antibacterial ionophores capable of targeting bacterial metal ion homeostasis and cellular redox balance. We propose that this novel and multitarget mechanism of PBT2 makes the development of cross-resistance to medically important antimicrobials unlikely.IMPORTANCE More antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance. Therefore, the elimination of antimicrobial crossover between human and veterinary medicine is of great interest. Unfortunately, the development of new antimicrobials is an expensive high-risk process fraught with difficulties. The repurposing of chemical agents provides a solution to this problem, and while many have not been originally developed as antimicrobials, they have been proven safe in clinical trials. PBT2, a zinc ionophore, is an experimental therapeutic that met safety criteria but failed efficacy checkpoints against both Alzheimer's and Huntington's diseases. It was recently found that PBT2 possessed potent antimicrobial activity, although the mechanism of bacterial cell death is unresolved. In this body of work, we show that PBT2 has multiple mechanisms of antimicrobial action, making the development of PBT2 resistance unlikely.
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- corona- and arterivirus replication can be inhibited by increased Zn2+ levels
corona- and arterivirus replication can be inhibited by increased Zn2+ levels, page-11
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