This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Amebiasis is the second leading parasitic cause of death worldwide. 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. Limited drug options, drug toxicities, and invasive forms of the disease complicate treatment. Entamoeba histolytica life cycle consists of the disease-causing trophozoite stage and the infectious cyst stage. My laboratory studies Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2), a bifunctional enzyme in the glycolytic pathway. We have shown that this enzyme is essential for the growth and survival of E. histolytica trophozoites. As it is a member of the microbial group III or """"""""iron activated"""""""" alcohol dehydrogenases it has little homology to eukaryotic enzymes. These fermentation enzymes appear to have been transferred horizontally from bacteria. ADHE enzymes likely different evolutionary origin from vertebrate enzymes suggests them as potential antimicrobial targets. Initial testing with commercially available cycloalkanols showed specific inhibition of EhADH2 activities and trophozoite survival at concentrations expected to be non-toxic to humans. We are currently testing amines, halides and tertiary alcohols. Novel searching of drug therapies is done using three strategies: a) test antibiotic extracts from surveyed Narragansett Bay marine bacteria and algae in collaboration with David Rowley, University of Rhode Island. b) custom-synthesis of pyrazoline and other organic compounds with low toxicity to humans in collaboration with Lauren Rossi, Roger Williams University. c) Biochemical and mutational analysis of EhADH2 to obtain structural/functional data for molecular modeling and drug design.
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