Abstract
Research on Giardia lamblia has accumulated large information about its molecular cell biology and infection biology. However, giardiasis is still one of the commonest parasitic diarrheal diseases affecting humans. Additionally, an alarming increase in cases refractory to conventional treatment has been reported in low prevalence settings. Consequently, efforts directed toward supporting the efficient use of alternative drugs, and the study of their molecular targets appears promising. Repurposing of proton pump inhibitors is effective in vitro against the parasite and the toxic activity is associated with the inhibition of the G. lamblia triosephosphate isomerase (GlTIM) via the formation of covalent adducts with cysteine residue at position 222. Herein, we evaluate the effectiveness of omeprazole in vitro and in situ on GlTIM mutants lacking the most superficial cysteines. We studied the influence on the glycolysis of Giardia trophozoites treated with omeprazole and characterized, for the first time, the morphological effect caused by this drug on the parasite. Our results support the effectiveness of omeprazole against GlTIM despite of the possibility to mutate the druggable amino acid targets as an adaptive response. Also, we further characterized the effect of omeprazole on trophozoites and discuss the possible mechanism involved in its antigiardial effect.
Highlights
Research on Giardia lamblia has accumulated large information about its molecular cell biology and infection biology
Wild-type (WT) G. lamblia triosephosphate isomerase (GlTIM) and double (Dmut) and triple (Tmut) mutants were efficiently purified to homogeneity; the His-tag and tobacco etch virus (TEV) protease cleavage systems yielded approximately 140, 300, and 108 mg of pure recombinant protein per liter of cell culture, respectively
The overall kinetics of Tmut resembled those of GlTIM derivatized with the thiol reactive reagent methyl methanethiosulfonate (MMTS) as previously demonstrated[19]
Summary
Research on Giardia lamblia has accumulated large information about its molecular cell biology and infection biology. Repurposing of proton pump inhibitors is effective in vitro against the parasite and the toxic activity is associated with the inhibition of the G. lamblia triosephosphate isomerase (GlTIM) via the formation of covalent adducts with cysteine residue at position 222. We studied the influence on the glycolysis of Giardia trophozoites treated with omeprazole and characterized, for the first time, the morphological effect caused by this drug on the parasite. The clinical impact of giardiasis seems to be stronger in the first 3 years of life and in undernourished or immunodeficient individuals[2,3] This parasitic disease continues to be the major cause of nonviral or bacterial diarrhea in humans and other vertebrates[4,5,6]. We hypothesize that when GlTIM is inactivated an energetic imbalance is provoked, which might be harmful for the parasite due to the effect on glycolysis and accumulation of toxic metabolites, such as methylglyoxal
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