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

Frontiers in Cellular and Infection Microbiology

Sharon Jan¹  James A. Tirtorahardjo¹  Naomi S. Morrissette²  Jerry J. Zhang³  Christopher I. Ma³  Rosa M. Andrade⁴  Sakura S. Schweizer⁵  Yanmiao Du⁶  Shawn A. C. Rosario⁶ 

[1] Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA, United States;Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, United States;Division of Infectious Diseases, Department of Medicine, University of California Irvine, Irvine, CA, United States;Division of Infectious Diseases, Department of Medicine, University of California Irvine, Irvine, CA, United States;Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA, United States;Division of Infectious Diseases, Department of Medicine, University of California Irvine, Irvine, CA, United States;School of Biological Sciences, University of California Irvine, Irvine, CA, United States;School of Biological Sciences, University of California Irvine, Irvine, CA, United States;

关键词: gold;    repurposing;    anti-parasitic;    resistance;    redox;    Toxoplasma;    auranofin;    superoxide;   

DOI  :  10.3389/fcimb.2021.618994

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

CC BY