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Multiple bactericidal mechanisms of the zinc ionophore PBT2

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dc.contributor.authorHarbison-Price, N.
dc.contributor.authorFerguson, S.A.
dc.contributor.authorHeikal, A.
dc.contributor.authorTaiaroa, G.
dc.contributor.authorHards, K.
dc.contributor.authorNakatani, Y.
dc.contributor.authorRennison, D.
dc.contributor.authorBrimble, M.A.
dc.contributor.authorEl-Deeb, I.M.
dc.contributor.authorBohlmann, L.
dc.contributor.authorMcDevitt, C.A.
dc.contributor.authorvon Itzstein, M.
dc.contributor.authorWalker, M.J.
dc.contributor.authorCook, G.M.
dc.contributor.editorDunman, P.
dc.date.issued2020
dc.descriptionPublished 18 March 2020
dc.description.abstractGlobally, 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.
dc.description.statementofresponsibilityNichaela Harbison-Price, Scott A. Ferguson, Adam Heikal, George Taiaroa, Kiel Hards ... Christopher A. McDevitt ... et al.
dc.identifier.citationmSphere, 2020; 5(2):e00157-20-1-e00157-20-15
dc.identifier.doi10.1128/msphere.00157-20
dc.identifier.issn2379-5042
dc.identifier.issn2379-5042
dc.identifier.orcidMcDevitt, C.A. [0000-0003-1596-4841]
dc.identifier.urihttp://hdl.handle.net/2440/127140
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.rights© 2020 Harbison-Price et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.source.urihttps://journals.asm.org/doi/10.1128/mSphere.00157-20
dc.subjectantimicrobial resistance
dc.subjectPBT2
dc.subjectzinc
dc.subjectmanganese
dc.subjectionophore
dc.subjectmetal ion homeostasis
dc.subjectoxidative stress
dc.titleMultiple bactericidal mechanisms of the zinc ionophore PBT2
dc.typeJournal article
pubs.publication-statusPublished

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