Giardia trophozoites have developed resistance mechanisms to currently available compounds, leading to treatment failures. In this context, the development of new additional agents is mandatory. Sirtuins, which are class III NAD+-dependent histone deacetylases, have been considered important targets for the development of new anti-parasitic drugs. Here, we evaluated the activity of KH-TFMDI, a novel 3-arylideneindolin-2-one-type sirtuin inhibitor, on G. intestinalis trophozoites. This compound decreased the trophozoite growth presenting an IC50 value lower than nicotinamide, a moderately active inhibitor of yeast and human sirtuins. Light and electron microscopy analysis showed the presence of multinucleated cell clusters suggesting that the cytokinesis could be compromised in treated trophozoites. Cell rounding, concomitantly with the folding of the ventro-lateral flange and flagella internalization, was also observed. These cells eventually died by a mechanism which lead to DNA/nuclear damage, formation of multi-lamellar bodies and annexin V binding on the parasite surface. Taken together, these data show that KH-TFMDI has significant effects against G. intestinalis trophozoites proliferation and structural organization and suggest that histone deacetylation pathway should be explored on this protozoon as target for chemotherapy.
Journal article
Int J Med Microbiol
03/2019
309
130 - 142
Automated quantitative fluorescence microscopy, Cell death, Class III NAD+-dependent histone deacetylases inhibitor, Electron microscopy, Giardia intestinalis, Proliferation, Antiprotozoal Agents, Caco-2 Cells, Cytokinesis, Giardia lamblia, Histone Deacetylase Inhibitors, Humans, Inhibitory Concentration 50, Microscopy, Microscopy, Electron, Parasitic Sensitivity Tests, Trophozoites