School of Medicine

Giardia lamblia is a protozoa which causes giardiasis, and is a major cause of parasitic diarrheal disease worldwide. Its methods of contamination and spreading are fecal-contaminated surfaces of materials, through ingestion of highly infectious cysts. Disease symptoms present in about half of infected individuals, and while typically transient, some patients remain symptomatic for extended periods. In the setting of immunodeficiency, chronic giardiasis can cause weight loss, malabsorption and increased mortality. Giardial infections are treated with metronidizole (Mz) which is a nitroimidazole compound, dosed 250mg three times a day for 5-10 days. Metronidazole is active against several anaerobic protozoa and bacteria, and operates by entering the cells as a prodrug via passive diffusion, later activated in the cytoplasm or an organelle within the different microbes. Metronidazole's mechanism of action in giardia required reduction of the 5-nitro group of the imidazole ring by ferredoxin leading to formation of toxic radicals that damage and inactivate critical molecules. Various straings of giardia lamblia exist, some only in a laboratory setting and others naturally occurring, that display variable degrees of resistance to metronidazole. Mz resistance in Giardia occurs in the laboratory and the mechanism of Mz resistance appear to be divers. In our research, three Mz sensitive (Mzs) strains, C6, 106, and 713, and six Mz resistant (Mzr) strains, C6a!, C6 0.5, 106c17, 106-2ID10, 713M3, 713c17 were used, along with a library of ~1,000 newly synthesized nitro compounds, to explore questions of resistance similarities between different strains, as well as the genetic basis of these resistance pathways. To address those questions, the degree of resistance by each strain toward each compound was first measured and the strains were analyzed to form a pattern, according to similar susceptability to the same compounds.