Entamoeba histolytica Adaption to Auranofin: A Phenotypic and Multi-Omics Characterization

Area of Science:

• Parasitology
• Drug Resistance
• Redox Biology

Background:

• Auranofin (AF) is an antirheumatic drug targeting thioredoxin reductase (TrxR) and effective against various pathogens.
• Entamoeba histolytica is a protozoan parasite causing amoebiasis.

Purpose of the Study:

• To investigate the development of resistance to auranofin in Entamoeba histolytica.
• To characterize the physiological and molecular changes in auranofin-adapted Entamoeba histolytica.

Main Methods:

• Gradual exposure of Entamoeba histolytica trophozoites to increasing concentrations of auranofin.
• Assessment of parasite growth, cytopathic activity, and sensitivity to oxidative stress, nitrosative stress, and metronidazole.
• Integrated transcriptomics and redoxomics analyses.

Main Results:

• Auranofin-adapted Entamoeba histolytica trophozoites (AFAT) exhibited impaired growth and reduced cytopathic activity.
• AFAT showed increased sensitivity to oxidative stress, nitrosative stress, and metronidazole compared to wild-type (WT) trophozoites.
• Transcriptomic and redoxomic data revealed that upregulated genes in AFAT encode proteins that were oxidized in acute AF exposure but not in AFAT, with lower reactive oxygen species and oxidized protein levels in AFAT.

Conclusions:

• Entamoeba histolytica can acquire resistance to auranofin through gradual drug exposure.
• Auranofin adaptation leads to altered redox homeostasis and increased susceptibility to other stressors and drugs.
• Thioredoxin reductase (TrxR) in Entamoeba histolytica is not central to the auranofin adaptation mechanism.