Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2

ABSTRACT 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 a...

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Autores principales:	Nichaela Harbison-Price, Scott A. Ferguson, Adam Heikal, George Taiaroa, Kiel Hards, Yoshio Nakatani, David Rennison, Margaret A. Brimble, Ibrahim M. El-Deeb, Lisa Bohlmann, Christopher A. McDevitt, Mark von Itzstein, Mark J. Walker, Gregory M. Cook
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	antimicrobial resistance PBT2 zinc manganese ionophore metal ion homeostasis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7ba6568165cb4f2489d265bf769ffb42
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spelling	oai:doaj.org-article:7ba6568165cb4f2489d265bf769ffb422021-11-15T15:29:16ZMultiple Bactericidal Mechanisms of the Zinc Ionophore PBT210.1128/mSphere.00157-202379-5042https://doaj.org/article/7ba6568165cb4f2489d265bf769ffb422020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00157-20https://doaj.org/toc/2379-5042ABSTRACT 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.Nichaela Harbison-PriceScott A. FergusonAdam HeikalGeorge TaiaroaKiel HardsYoshio NakataniDavid RennisonMargaret A. BrimbleIbrahim M. El-DeebLisa BohlmannChristopher A. McDevittMark von ItzsteinMark J. WalkerGregory M. CookAmerican Society for Microbiologyarticleantimicrobial resistancePBT2zincmanganeseionophoremetal ion homeostasisMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial resistance PBT2 zinc manganese ionophore metal ion homeostasis Microbiology QR1-502
spellingShingle	antimicrobial resistance PBT2 zinc manganese ionophore metal ion homeostasis Microbiology QR1-502 Nichaela Harbison-Price Scott A. Ferguson Adam Heikal George Taiaroa Kiel Hards Yoshio Nakatani David Rennison Margaret A. Brimble Ibrahim M. El-Deeb Lisa Bohlmann Christopher A. McDevitt Mark von Itzstein Mark J. Walker Gregory M. Cook Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
description	ABSTRACT 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.
format	article
author	Nichaela Harbison-Price Scott A. Ferguson Adam Heikal George Taiaroa Kiel Hards Yoshio Nakatani David Rennison Margaret A. Brimble Ibrahim M. El-Deeb Lisa Bohlmann Christopher A. McDevitt Mark von Itzstein Mark J. Walker Gregory M. Cook
author_facet	Nichaela Harbison-Price Scott A. Ferguson Adam Heikal George Taiaroa Kiel Hards Yoshio Nakatani David Rennison Margaret A. Brimble Ibrahim M. El-Deeb Lisa Bohlmann Christopher A. McDevitt Mark von Itzstein Mark J. Walker Gregory M. Cook
author_sort	Nichaela Harbison-Price
title	Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
title_short	Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
title_full	Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
title_fullStr	Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
title_full_unstemmed	Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
title_sort	multiple bactericidal mechanisms of the zinc ionophore pbt2
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/7ba6568165cb4f2489d265bf769ffb42
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Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2

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