Antiproliferation and Antiencystation Effect of Class II Histone Deacetylase Inhibitors on Acanthamoeba castellanii

Abstract

Acanthamoeba is a ubiquitous and free-living protozoan pathogen responsible for causing Acanthamoeba 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 Acanthamoeba 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 Acanthamoeba 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 Acanthamoeba. Synthetic class II HDACi FFK29 (IIa selective) and MPK576 (IIb selective) dose-dependently decreased the viability of Acanthamoeba trophozoites. While these HDACi demonstrated a negligible effect on the viability of mature cysts, Acanthamoeba 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 Acanthamoeba, thus highlighting their enormous potential for further development.

Synthesis and Evaluation of Novel DNA Minor Groove Binders as Antiamoebic Agents

“…Diethyl ether (30 mL) was added, and the product was collected by filtration, washed with ether, and dried under reduced pressure to produce the product as white solid crystals. Yield (75%); 1 H NMR (CHLOROFORM-d) δ 1.77 (2H, m, CH 2 ), 2.37 (6H, s, NCH 3 ), 2.56 (2H, t, NCH 2 ), 3.50 (2H, q, CONH-CH 2 ), 4.01 (3H, s, NCH 3 ), 6.98 (1H, d, Ar-H), 7.53 (1H, d, Ar-H), 8.67 (1H, s, CONH); 13…”

“…The solvent was evaporated under reduced pressure, and the crude product was re-crystallized by using water:ethanol (80:20%), filtered, and washed with hexane to obtain the product in the form of white solid crystals. Yield (70%); 1 H NMR (CHLOROFORM-d) δ 1.79 (2H, m, CH 2 ), 2.53 (4H, s, NCH 2 ), 2.57 (2H, t, NCH 2 ), 3.50 (2H, q, CONH-CH 2 ), 3.76 (4H, t, OCH 2 ), 4.00 (3H, s, NCH 3 ), 7.10 (1H, d, Ar-H), 7.54 (1H, d, Ar-H), 7.94 (1H, s, CONH); 13…”

“…The solvent was removed under reduced pressure, and the crude product obtained was purified on basified silica, using a 5:94:1 solution of MeOH/EA/TEA to obtain the product as white solid. Yield (68%); 1…”

“…Commonly found in the environment all around the world is the free-living, opportunistic protozoa Acanthamoeba [ 1 , 2 , 3 ]. Acanthamoeba castellanii is responsible for the fatal central nervous infection granulomatous amoebic encephalitis (GAE) and the sight-threatening infection Acanthamoeba keratitis (AK) [ 1 , 4 ]. This protozoon exists in two stages: an active, infective trophozoite stage; and a dormant, inactive cyst stage [ 4 ].…”

“…Currently, a combination drug therapy is used to fight against AK; a combination treatment of propamidine isethionate and neomycin is used as a topical treatment option [ 4 ]. Additionally, biguanide and diamidine antimicrobial, antiseptic, antiparasitic, antibiotic, and antifungal agents are used for clinically resistant cases [ 1 ]. However, more efficient, biologically safe treatments are needed.…”