Investigator: Avelina Espinosa, Roger Williams University

Scientific Theme: Molecular Toxicology

Abstract: Anaerobic protozoan parasites share physiological and biochemical features (e.g. carbohydrate metabolism and cytosolic fermentation enzymes) essential to survive in their hosts. Understanding the evolutionary adaptations of glycolytic enzymes to luminal environments -in the context of diverse host conditions for anaerobic metabolism- can lead to the development of new drugs and/or improve treatments for infectious diseases. Amebiasis is the third leading parasitic cause of death worldwide. As an anaerobic eukaryote, its causative agent, Entamoeba histolytica lacks mitochondria and obtains energy from fermenting glucose, with carbon dioxide, acetate, and ethanol as end products. This metabolic pathway provides targets for developing anti-infective agents (ADHE alcohol/aldehyde dehydrogenases). During the past 15 years, Espinosa et al. have shown that the bifunctional Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2) is a glycolytic enzyme essential for the survival of the trophozoite in the luminal environment of humans; thus, an ideal target for the development of anti-amebic agents. Because ADHE enzymes are found in bacteria (i.e. group-A-streptococcus, Pasteurella multocida, E. coli, Clostridium perfringens, Clostridium difficile), and protozoan parasites such as E. histolytica, and differ phylogenetically from human enzymes, ADHE targeting chemotherapeutic agents could effectively treat a broad range of human diseases. This proposal aims to a) characterize molecular, biochemical and structural properties of alcohol/aldehyde dehydrogenases (ADHE) to design customized antiamebic agents; b) Test novel pyrazolines as inhibitors of trophozoite growth and EhADH2 enzyme activities. Studying the adaptations of anaerobic pathogens to the luminal environment can change the classical view of infectious diseases to an evolutionary understanding of the ecological association between microbionts. By analyzing the structural properties of model anaerobic enzymes essential for the survival of the human pathogen Entamoeba histolytica to the human luminal environment we can highlight the importance of an evolutionary perspective in the education of students interested in pursuing health related professions.

Human Health Relevance: EhADH2 is the ideal target for the development of a novel classes of inhibitors to treat amebiasis, the gastrointestinal infection caused by E. histolytic that is estimated to cause 100,000 deaths per year. This study will provide hands-on experience to help students develop an understanding of the scientific method, the critical thinking and technical skills needed to pursue a career in science or in health related areas.