Screening and evaluation of potential histone deacetylase inhibitors against Babesia infections

Babesia spp., a group of blood protozoa transmitted via the bites of tick vectors, cause enormous economic losses for livestock industry and pose significant risk to public health. Currently, the drugs available for treating babesiosis are limited and possess certain toxicity, making the discovery of new and safer drug candidates an urgent priority. Inhibitors targeting histone deacetylase (HDACs) have attracted increasing attention for its antiparasitic effects as a drug targeting epigenetic regulatory enzymes. However, little is known about the effects of HDAC inhibitors on Babesia parasites. Here, 69 compounds targeting HDAC were evaluated for inhibiting Babesia xinjiangensis (B. xinjiangensis) growth in vitro. Among them, 7 compounds (at 2 μM) exhibited high growth inhibition (≥50%) and the cytotoxicity on MDOK cells of the compounds was assessed subsequently. The half-maximal inhibitory concentration (IC₅₀) values of the seven compounds for MDOK cells are greater than 3 μM. Two compounds, namely panobinostat and belinostat were chosen for in vivo assays. In our study, panobinostat and belinostat demonstrated outstanding activity in vitro at the nanomolar level. The IC₅₀ values of panobinostat and belinostat were determined to be 30(±2) nM and 235(±21) nM at 48 h, respectively, and both exhibited low cytotoxicity, with IC₅₀ values of 3 (±0.4) μM and 20 (±3) μM respectively. In addition, panobinostat effectively and safely inhibited B. microti growth in BALB/c mice. Our findings support that panobinostat is a potential alternative drug to control babesiosis.