Identification of New Drugs Against Amebiasis by Targeting Protozoan Anaerobic Metabolism (2009 - Present)

Investigator:  Avelina Espinosa, Roger Williams University 
Mentor: Dan Eichinger, New York University

Abstract:  Amebiasis is the second leading parasitic cause of death worldwide and its causative agent is the anaerobic protozoan Entamoeba histolytica. Approximately 12% of the world’s population is infected. Clinical symptoms manifest in nearly 50 million people annually, causing 100,000 fatalities worldwide. Enteric protozoa are included among the category B agents due to their potential for dissemination through compromised food and water supplies in the United States. Currently, critical knowledge is lacking regarding host and environmental factors related to amebic pathogenicity. Limited drug options, drug toxicities, and invasive forms of the disease complicate treatment.

This student training grant will focus on (1) assessing the effects of defined metal chelators and novel marine compounds against EhADH2; (2) assessing the effects of defined metal chelators and screening for novel compounds that inhibit growth of live Entamoeba spp. and (3) training undergraduate students to facilitate their entry into health related graduate programs and professions. Metal-dependence studies will focus on the essential amebic enzyme Entamoeba histolytica alcohol dehydrogenase E (EhADH2). The EhADH2 iron-binding domain will be studied and compared to the E. invadens homologous enzyme as it has higher resistance to inactivation by oxygen and needs lower temperatures to function. Molecular, biochemical and physiological growth conditions will be used to investigate the effects of iron-limitation as a feasible anti-amebic therapy. For drug discovery, an array of natural products will be tested as novel inhibitors of trophozoite growth and EhADH2 function. Secondary metabolites produced by marine actinomycetes will be a special focus since these represent a chemically rich and completely untapped resource for anti-protozoan drug discovery.  Exciting preliminary studies have already led to the discovery of three structurally distinct metabolites that potently inhibit amebic growth.  Specific Aims: 1) Assess the effects of defined metal chelators and novel marine compounds against EhADH2 and 2) Assess the effects of defined metal chelators and screen for novel compounds that inhibit growth of live Entamoeba spp.