Application of Histone Deacetylase Inhibitors MPK472 and KSK64 as a Potential Treatment Option for Acanthamoeba Keratitis

Abstract

Treatment of Acanthamoeba keratitis (AK) is difficult because Acanthamoeba cysts are resistant to drugs and as such, successful treatment requires an effective approach that inhibits cyst formation. Histone deacetylase inhibitors (HDACi) are involved in cell proliferation, differentiation, and apoptotic cell death. In this study, the effects of HDACi such as MPK472 and KSK64 on A. castellanii trophozoites and cysts were observed. MPK472 and KSK64 showed at least 60% amoebicidal activity against Acanthamoeba trophozoite at a concentration of 10 μM upon 8 h. Neither of the two HDACi affected mature cysts, but significant amoebicidal activities (36.4% and 33.9%) were observed against encysting Acanthamoeba following treatment with 5 and 10 μM HDACi for 24 h. Light microscopy and transmission electron microscopy results confirmed that the encystation of Acanthamoeba was inhibited by the two HDACi. In addition to this, low cytopathic effects on human corneal epithelial (HCE) cells were observed following MPK472 and KSK64 treatment for 24 h. Our results indicate that the HDACi MPK472 and KSK64 could be used as new candidates for the development of an optimal therapeutic option for AK.

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

“…A number of reports have demonstrated that histone modifications (or chromatin remodeling) play important roles in the life cycle of several genera of amoeba, including Acanthamoeba , Entamoeba , and Dictyostellium . HDACi inhibited the encystation of Acanthamoeba and Entamoeba . Additionally, small-molecule inhibitors of mammalian HDAC have shown a synergistic amoebicidal effect with PHMB and an amoebicidal effect by themselves .…”

“…Additionally, recent studies have shown that parasitic HDACs and HATs are crucial for adapting to host environmental conditions, host immune response evasion, and phenotype alterations during various stages of their complex life cycle . Given the striking homology between mammalian and parasitic HDACs, several studies have tested the therapeutic efficacy of mammalian HDACi against various parasites, including Trypanosoma , Toxoplasma , Schistosoma , Leishmania , and Plasmodium . , Several Food & Drug Administration (FDA)-approved HDACi hindered the growth of various Plasmodium species, including the drug-resistant strain, and were active against multiple life-cycle stages of P. falciparum . ,− Recently, it has been reported that class II HDACi showed an amoebicidal effect without cytotoxicity on the human corneal cells . Class II HDACi are a safer treatment alternative than class I HDACi, since their genomic effect on host cells is negligible, as described above.…”

Infectious Keratitis: An Update on Role of Epigenetics

“…Similarly, attenuation of fungal keratitis in mice by histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA) has been recently reported by Xiaohua Li et al (4),. Also, Hae-Ahm Lee et al (61) have recently shown that histone deacetylase inhibitors MPK472 and KSK64 can be potential therapeutic targets for Acanthamoeba keratitis, which otherwise is difficult to treat because of cyst formation. These HDACs inhibit the encystation of Acanthamoeba and have low cytopathic effects on human corneal epithelial cells, and therefore can be promising epidrugs for Acanthamoeba induced keratitis.…”

Adverse Outcome Pathway on histone deacetylase inhibition leading to testicular atrophy

“…Other potential applications of the AOP include the risk assessment of biocides or pesticides, considering that HDAC inhibitors are being investigated as insecticides or amoebicides [Bagnall et al, 2017;Lee et al, 2020].…”