Abstract
Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, a long treatment course, and the need for an additional drug to prevent cyst-mediated transmission. E. histolytica possesses a kinome with approximately 300-400 members, some of which have been previously studied as potential targets for the development of amoebicidal drug candidates. However, while these efforts have uncovered novel potent inhibitors of E. histolytica kinases, none have resulted in approved drugs. In this study we took the alternative approach of testing a set of twelve previously FDA-approved antineoplastic kinase inhibitors against E. histolytica trophozoites in vitro. This resulted in the identification of dasatinib, bosutinib, and ibrutinib as amoebicidal agents at low-micromolar concentrations. Next, we utilized a recently developed computational tool to identify twelve additional drugs with human protein target profiles similar to the three initial hits. Testing of these additional twelve drugs led to the identification of ponatinib, neratinib, and olmutinib were identified as highly potent, with EC50 values in the sub-micromolar range. All of these six drugs were found to kill E. histolytica trophozoites as rapidly as metronidazole. Furthermore, ibrutinib was found to kill the transmissible cyst stage of the model organism E. invadens. Ibrutinib thus possesses both amoebicidal and cysticidal properties, in contrast to all drugs used in the current therapeutic strategy. These findings together reveal antineoplastic kinase inhibitors as a highly promising class of potent drugs against this widespread and devastating disease.
Highlights
Entamoeba histolytica is a parasitic amoeba which infects an estimated 50 million people worldwide, resulting in around 70,000 deaths per year [1]
In order to identify anti-amoebic activity among antineoplastic kinase inhibitors, a selection of 12 drugs was screened against E. histolytica trophozoites in vitro
E. histolytica trophozoites were seeded into 96-well plates along with a serially-diluted range of drug concentrations
Summary
Entamoeba histolytica is a parasitic amoeba which infects an estimated 50 million people worldwide, resulting in around 70,000 deaths per year [1]. E. histolytica infection is known as amoebiasis and primarily affects the intestinal tract in humans, most commonly causing symptoms such as abdominal pain, bloody diarrhea, and colitis [2]. Symptoms can develop when compromise of the mucosal layer allows it to come into contact with the intestinal wall, at which point it invades the wall and surrounding tissue causing characteristic ‘flask-shaped ulcers’ [3]. Due to this mode of transmission E. histolytica disproportionately affects populations experiencing sanitation problems associated with low socioeconomic status [2,4,5]. Malnutrition is known to be a major risk factor for amoebiasis, especially in children [6]
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