Investigation of Giradiasis Using Click Chemistry Techniques

Giardiasis is an important cause of waterborne illness resulting from a one-celled microscopic parasite, Giardia intestinalis (also known as Giardia lamblia). The pathogenic cyst form is protected by an outer shell and can survive outside the body in the environment for long periods of time. It is resistant to water treatment processes such as ozonolysis and chlorination. <P> Giardiasis is recognized as one of the most prevalent causes of waterborne illness originating from both drinking water and recreational water activities. Giardia is found throughout the world and in every region of the United States. Furthermore, G. lamblia is a credible bioterrorism threat because it is easily obtained, has a very low infectious dose, and causes severe symptoms such as abdominal pain, diarrhea, and nausea. <P> Metronidazole is the current first line treatment of giardiasis. However, clinical resistance of Giardia to metronidazole has been reported. Although several other drugs are currently available, new, potent, and selective (i.e., devoid of serious side effects) anti-parasitic medications are needed to combat resistance and improve efficacy. <P> This project aims to develop such new drugs employing click chemistry, a strategy for rapid and efficient assembly of compounds with desired function. Additionally, click chemistry-based bioconjugation techniques will be used to study the mode of action of the active compounds. The screening libraries will be synthesized using catalytic azide-alkyne cycloadditions and will be assayed against both the wild type and the resistant Giardia strains. <P> The straightforward syntheses we will employ guarantee rapid structure-activity profiling and improvement of the activity of the most promising leads. To study the mechanism of action of the active compounds, we will identify the covalent adducts of nitroazoles with Giardia proteins and will also study the differences in protein composition of the wild type and metronidazole-resistant Giardia strains. <P> We will study electrochemically the formation of amino acid-metronidazole adducts and determine their exact chemical structures.