title: A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target.
abstract: Entamoeba histolytica, a protozoan intestinal parasite, is the causative agent of human amebiasis. Amebiasis is the fourth leading cause of death and the third leading cause of morbidity due to protozoan infections worldwide(1), resulting in ~70,000 deaths annually. E. histolytica has been listed by the National Institutes of Health as a category B priority biodefense pathogen in the United States. Treatment relies on metronidazole(2), which has adverse effects(3), and potential resistance of E. histolytica to the drug is an increasing concern(4,5). To facilitate drug screening for this anaerobic protozoan, we developed and validated an automated, high-throughput screen (HTS). This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as active against E. histolytica in culture. Auranofin was ten times more potent against E. histolytica than metronidazole. Transcriptional profiling and thioredoxin reductase assays suggested that auranofin targets the E. histolytica thioredoxin reductase, preventing the reduction of thioredoxin and enhancing sensitivity of trophozoites to reactive oxygen-mediated killing. In a mouse model of amebic colitis and a hamster model of amebic liver abscess, oral auranofin markedly decreased the number of parasites, the detrimental host inflammatory response and hepatic damage. This new use of auranofin represents a promising therapy for amebiasis, and the drug has been granted orphan-drug status from the FDA.
authors.affiliation: Sandler Center for Drug Discovery, University of California–San Francisco, San Francisco, California, USA. anjan.debnath@ucsf.edu
authors.forename: Anjan
authors.initials: A
authors.lastname: Debnath
authors.forename: Derek
authors.initials: D
authors.lastname: Parsonage
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Andrade
authors.forename: Chen
authors.initials: C
authors.lastname: He
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Cobo
authors.forename: Ken
authors.initials: K
authors.lastname: Hirata
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.forename: Guillermina
authors.initials: G
authors.lastname: García-Rivera
authors.forename: Esther
authors.initials: E
authors.lastname: Orozco
authors.forename: Máximo B
authors.initials: MB
authors.lastname: Martínez
authors.forename: Shamila S
authors.initials: SS
authors.lastname: Gunatilleke
authors.forename: Amy M
authors.initials: AM
authors.lastname: Barrios
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Poole
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Reed
mesh_terms: D000818:Animals; D001310:Auranofin / Q000494:pharmacology; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D004748:Entamoeba histolytica / Q000187:drug effects* / Q000235:genetics; D057166:High-Throughput Screening Assays; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors
chemical_list: D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase