Abstract
Theileria equi and Babesia caballi are the causative agents of equine piroplasmosis (EP). Currently, imidocarb dipropionate (ID) is the only available drug for treating the clinical form of EP. Serious side effects and incomplete clearance of infection is a major drawback of ID. Heat-shock proteins (Hsp) play a vital role in the life cycle of these haemoprotozoans by preventing alteration in protein conformation. These Hsp are activated during transmission of EP sporozoites from the tick vector (poikilotherm) to the natural host (homeotherm) and facilitate parasite survival. In the present study, we targeted the heat shock protein 90 (Hsp-90) pathway of T. equi and B. caballi by using its inhibitor drug - novobiocin. Dose-dependent efficacy of novobiocin on the growth of T. equi and B. caballi was observed in in vitro culture. Additionally, we examined dose-dependent cell cytotoxicity on host peripheral mononuclear cells (PBMCs) and haemolytic activity on equine red blood cells (RBC). In vivo organ toxicity of novobiocin was also assessed in a mouse model. The IC50 (50 % inhibitory concentration) value of novobiocin against T. equi and B. caballi was 165 μM and 84.85 μM, respectively. Novobiocin significantly arrested the in vitro growth of T. equi and B. caballi parasites at 100 μM and 200 μM drug concentration, respectively. In vitro treated parasites had distorted nuclear material and showed no further viability. Based on the equine PBMCs and RBC, the drug was found to be safe even at 1000 μM concentration and the CC50 (50 % cytotoxicity concentration) values were 11.63 mM and 261.97 mM. Very high specific selective index (SSI) values (70.47 and 1587) were observed for equine PBMCs and RBC, respectively. Organ-specific biochemical markers and histopathological examination indicated no adverse effect of the drug at a dose rate of 50 mg kg body weight in the mouse model. The results demonstrate the growth inhibitory effect of novobiocin against T. equi and B. caballi parasites and its safety for host cell lines with very high SSI. Hence, it can be inferred that the Theileria/Babesia Hsp-90 family are potential drug targets worthy of further investigation.
Highlights
Theileria equi and Babesia caballi are the causative agents for equine piroplasmosis (EP)
It can be inferred that Theileria/Babesia Heat shock protein (Hsp)-90 family are the potential drug targets worthy of further investigation
Organ toxicity of novobiocin was accessed in mice model and no adverse effect of the drug was observed at a dose rate of 50 mg/kg body weight
Summary
Theileria equi and Babesia caballi are the causative agents for equine piroplasmosis (EP). Heat-shock proteins (HSP) play a vital role in the life cycle of these haemoprtozoa by way of preventing alteration in protein conformation These HSPs are activated during transfer of EP sporozoites from tick vector (poikilotherm) to natural host (homeotherm) and helped it for survival. In this present study we have targeted the heat shock protein 90 pathway of T. equi and B. caballi by its inhibitor drug - novobiocin. Protozoa specific heat shock proteins 90 (Hsp-90) get activated during such temperature change and plays a vital role in the life-cycle of parasite within host [1, 22].In spite of fact that Hsp-90 has a critical role in its multiplication inside the equine RBCs, not much efforts have been exerted in pursuing researches against this drug target [6]. Keeping in view anti-bacterial, anti-cancerous and anti-plasmodial potential of novobiocin drug, this present study was planned for investigating its anti-T. equi/B. caballi activity and invitro/in-vivo cytotoxicity or organ toxicity
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