Anaerobic Enzymes as Targets of Novel Anti-infective Therapeutics (2012 - Present)

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

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, E. 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 antiinfective agents (ADHE alcohol/aldehyde dehydrogenases). Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2) is a glycolytic enzyme essential for the survival of the trophozoite in the luminal environment. 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 the genetic, biochemical and structural properties of alcohol/aldehyde dehydrogenases (ADHE); b) synthesize novel synthetic pyrazolines capable of inhibiting pathogenic growth and ADHE enzymes (e.g. iron chelation or alcohol analogs); c) and test the efficiency and safety of these chemicals in vitro. Studying the adaptations of anaerobic pathogens to the luminal environment can change the classical view of infectious diseases as ‘evolutionary arms races’ to an evolutionary understanding of the ecological association between hosts and microbiota. 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 expand our knowledge of a novel family of enzymes and highlight the importance of an evolutionary/biological perspective in the education of students interested in pursuing health related professions.