Antiproliferation and Antiencystation Effect of Class II Histone Deacetylase Inhibitors on <i>Acanthamoeba castellanii</i>

Abstract

<i>Acanthamoeba</i> is a ubiquitous and free-living protozoan pathogen responsible for causing <i>Acanthamoeba</i> keratitis (AK), a severe corneal infection inflicting immense pain that can result in permanent blindness. A drug-based treatment of AK has remained arduous because <i>Acanthamoeba</i> trophozoites undergo encystment to become highly drug-resistant cysts upon exposure to harsh environmental conditions such as amoebicidal agents (e.g., polyhexanide, chloroquine, and chlorohexidine). As such, drugs that block the <i>Acanthamoeba</i> encystation process could result in a successful AK treatment. Histone deacetylase inhibitors (HDACi) have recently emerged as novel therapeutic options for treating various protozoan and parasitic diseases. Here, we investigated whether novel HDACi suppress the proliferation and encystation of <i>Acanthamoeba</i>. Synthetic class II HDACi FFK29 (IIa selective) and MPK576 (IIb selective) dose-dependently decreased the viability of <i>Acanthamoeba</i> trophozoites. While these HDACi demonstrated a negligible effect on the viability of mature cysts, <i>Acanthamoeba</i> encystation was significantly inhibited by these HDACi. Apoptosis was slightly increased in trophozoites after a treatment with these HDACi, whereas cysts were unaffected by the HDACi exposure. The viability of human corneal cells was not affected by HDACi concentrations up to 10 μmol/L. In conclusion, these synthetic HDACi demonstrated potent amoebicidal effects and inhibited the growth and encystation of <i>Acanthamoeba</i>, thus highlighting their enormous potential for further development.