Fighting Drug Resistance in Giardia intestinalis: In Vitro Testing of Novel Antibiotics
Additional Funding Sources
TS is the recipient of a INBRE undergraduate research fellowship. TS and LJM also received support from the Ralph Jones Premedical Fellowship. This project was supported by NIH grant 1R15GM125065-01 to KC and JT. The project was also supported by the IDeA NIH NIGMS under Grants #P20GM103408 and P20GM109095. Additional support was provided by the BSU Biomolecular Research Center and Institute for Translational Health Sciences (ITHS).
Presentation Date
7-2018
Abstract
Annually, more than 280 million people worldwide develop symptomatic Giardia intestinalis (GI) infections, making it one of the most prevalent parasitic diseases. The parasite colonizes the small intestine, causing diarrhea, stomach cramps, vomiting, weight loss, and fatigue. While rarely fatal, the interruption of nutrient absorption can cause developmental delays in children. The current treatment generally relies on nitroazole drugs like metronidazole (MTZ), tinidazole, and albendazole. Drug resistance is a pressing issue, making the development of alternative treatments important. Our prior work has shown that the parasite enzyme 5’ Methylthioadenosine nucleosidase (MTN) is a good target for drug development. MTN inhibition would interrupt critical methionine and adenine recycling in GI, leading to cell death. In silico screening of potential MTN binding drugs has identified a set of thirty-three possible inhibitors that could ultimately have antiparasitic activity. Preliminary in vitro cytotoxicity data indicate that four compounds out of the thirty-three potential MTN inhibitors show micromolar IC50 values. These compounds will serve as leads for future drug optimization and testing against both MTZ sensitive and MTZ resistant parasites to examine their ability to overcome drug resistant infections.
Fighting Drug Resistance in Giardia intestinalis: In Vitro Testing of Novel Antibiotics
Annually, more than 280 million people worldwide develop symptomatic Giardia intestinalis (GI) infections, making it one of the most prevalent parasitic diseases. The parasite colonizes the small intestine, causing diarrhea, stomach cramps, vomiting, weight loss, and fatigue. While rarely fatal, the interruption of nutrient absorption can cause developmental delays in children. The current treatment generally relies on nitroazole drugs like metronidazole (MTZ), tinidazole, and albendazole. Drug resistance is a pressing issue, making the development of alternative treatments important. Our prior work has shown that the parasite enzyme 5’ Methylthioadenosine nucleosidase (MTN) is a good target for drug development. MTN inhibition would interrupt critical methionine and adenine recycling in GI, leading to cell death. In silico screening of potential MTN binding drugs has identified a set of thirty-three possible inhibitors that could ultimately have antiparasitic activity. Preliminary in vitro cytotoxicity data indicate that four compounds out of the thirty-three potential MTN inhibitors show micromolar IC50 values. These compounds will serve as leads for future drug optimization and testing against both MTZ sensitive and MTZ resistant parasites to examine their ability to overcome drug resistant infections.
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