Entamoeba histolytica is an important human pathogen with significant impact on a global scale. E. histolytica infects 500 million people annually, causes invasive disease in 50 million people and results in 100,000 deaths making it a leading parasitic cause of death worldwide. Despite the human burden of amebiasis there is a paucity of antimicrobials available, with treatment dependent on a single class of agents and emergence of resistance an ongoing concern. Additionally, there are no significant pipelines for novel drug development against this neglected tropical disease. Thus, there is a critical need for new drugs against Entamoeba. To circumvent the long and costly standard drug development route, we chose a compound screening approach based on phenotypic readouts of cell viability and stage conversion. The libraries we will screen have two advantages: previous success in parasitic systems and largely from repurposed FDA-approved compounds. These advantages combined with the drug development expertise at Stanford predict a successful outcome. We propose the following:
Aim 1 : Drug screen against Entamoeba trophozoites and encystation (early cysts);
and Aim 2 Confirmation of select hits. Successful completion of these aims will identify lead compounds/series with activity against Entamoeba. These compounds will give insights into the cell biology of Entamoeba development and eventually can also provide a beginning pipeline for drug development efforts. Based on our experience with Entamoeba development and a cadre of outstanding colleagues and collaborators, we are confident of a successful outcome.
Entamoeba histolytica is an important pathogen, which impacts human health on a global scale. Conversion between the trophozoite and cyst stage is central to parasite biology and responsible for disease dissemination and pathogenesis. Our long-term goals are to identify the molecular signals that initiate stage conversion. To this end, we will perform a compound screen to identify compounds with activity against Entamoeba and which target the encystation pathway. Our efforts will provide insights into the cell biology of Entamoeba stage conversion and could eventually aid in the development of new therapeutic options against this neglected tropical disease.
| Ehrenkaufer, Gretchen M; Suresh, Susmitha; Solow-Cordero, David et al. (2018) High-Throughput Screening of Entamoeba Identifies Compounds Which Target Both Life Cycle Stages and Which Are Effective Against Metronidazole Resistant Parasites. Front Cell Infect Microbiol 8:276 |
