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Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase

Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated auranofin resistant T. gondii lines throug...

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Autores principales: Ma, Christopher I., Tirtorahardjo, James A., Jan, Sharon, Schweizer, Sakura S., Rosario, Shawn A. C., Du, Yanmiao, Zhang, Jerry J., Morrissette, Naomi S., Andrade, Rosa M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017268/
https://www.ncbi.nlm.nih.gov/pubmed/33816332
http://dx.doi.org/10.3389/fcimb.2021.618994
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author Ma, Christopher I.
Tirtorahardjo, James A.
Jan, Sharon
Schweizer, Sakura S.
Rosario, Shawn A. C.
Du, Yanmiao
Zhang, Jerry J.
Morrissette, Naomi S.
Andrade, Rosa M.
author_facet Ma, Christopher I.
Tirtorahardjo, James A.
Jan, Sharon
Schweizer, Sakura S.
Rosario, Shawn A. C.
Du, Yanmiao
Zhang, Jerry J.
Morrissette, Naomi S.
Andrade, Rosa M.
author_sort Ma, Christopher I.
collection PubMed
description Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated auranofin resistant T. gondii lines through chemical mutagenesis to identify the molecular target of this drug. Resistant clones were confirmed with a competition assay using wild-type T. gondii expressing yellow fluorescence protein (YFP) as a reference strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of our resistant lines. Subsequent whole genomic sequencing analysis (WGS) did not reveal a consensus resistance locus, although many have point mutations in genes encoding redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient to confer resistance when introduced into wild-type parasites. Resistant clones accumulated less ROS than their wild type counterparts. Our results demonstrate that resistance to auranofin in T. gondii enhances its ability to abate oxidative stress through diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin anti-parasitic activity as disruption of redox homeostasis.
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spelling pubmed-80172682021-04-03 Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase Ma, Christopher I. Tirtorahardjo, James A. Jan, Sharon Schweizer, Sakura S. Rosario, Shawn A. C. Du, Yanmiao Zhang, Jerry J. Morrissette, Naomi S. Andrade, Rosa M. Front Cell Infect Microbiol Cellular and Infection Microbiology Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated auranofin resistant T. gondii lines through chemical mutagenesis to identify the molecular target of this drug. Resistant clones were confirmed with a competition assay using wild-type T. gondii expressing yellow fluorescence protein (YFP) as a reference strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of our resistant lines. Subsequent whole genomic sequencing analysis (WGS) did not reveal a consensus resistance locus, although many have point mutations in genes encoding redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient to confer resistance when introduced into wild-type parasites. Resistant clones accumulated less ROS than their wild type counterparts. Our results demonstrate that resistance to auranofin in T. gondii enhances its ability to abate oxidative stress through diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin anti-parasitic activity as disruption of redox homeostasis. Frontiers Media S.A. 2021-03-19 /pmc/articles/PMC8017268/ /pubmed/33816332 http://dx.doi.org/10.3389/fcimb.2021.618994 Text en Copyright © 2021 Ma, Tirtorahardjo, Jan, Schweizer, Rosario, Du, Zhang, Morrissette and Andrade http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Ma, Christopher I.
Tirtorahardjo, James A.
Jan, Sharon
Schweizer, Sakura S.
Rosario, Shawn A. C.
Du, Yanmiao
Zhang, Jerry J.
Morrissette, Naomi S.
Andrade, Rosa M.
Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
title Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
title_full Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
title_fullStr Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
title_full_unstemmed Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
title_short Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
title_sort auranofin resistance in toxoplasma gondii decreases the accumulation of reactive oxygen species but does not target parasite thioredoxin reductase
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017268/
https://www.ncbi.nlm.nih.gov/pubmed/33816332
http://dx.doi.org/10.3389/fcimb.2021.618994
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