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A HIGH THROUGHPUT DRUG SCREEN FOR E. HISTOLYTICA IDENTIFIES A NEW LEAD AND TARGET

Wednesday, 18th of July 2012

• A HIGH-THROUGHPUT DRUG SCREEN FOR ENTAMOEBA HISTOLYTICA IDENTIFIES A NEW LEAD AND TARGET

Anjan Debnath,¹ Derek Parsonage,² Rosa M Andrade,^{3, 4} Chen He,³ Eduardo R Cobo,³ Ken Hirata,³ Steven Chen,⁵ Guillermina García-Rivera,⁶ Esther Orozco,⁶ Máximo B Martínez,⁶ Shamila S Gunatilleke,¹ Amy M Barrios,⁷ Michelle R Arkin,⁵ Leslie B Poole,² James H McKerrow¹ & Sharon L Reed^{3, 4}

Received 03 October 2011 Accepted 30 March 2012 Published online 20 May 2012

Excerpt below; full text available to subscribers of Nature Medicine

Also at http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2758.html

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 worldwide¹, 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 metronidazole², which has adverse effects³, 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.