Anti-piroplasmic activity of novobiocin as heat shock protein 90 inhibitor against in vitro cultured Theileria equi and Babesia caballi parasites.
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 IC (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 CC (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.
Copyright © 2021 Elsevier GmbH. All rights reserved.
Publication Date: 2021-02-27 PubMed ID: 33677232DOI: 10.1016/j.ttbdis.2021.101696Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research paper is a study on the potential of novobiocin in inhibiting the growth of Theileria equi and Babesia caballi parasites, the causative agents of equine piroplasmosis. The tests were carried out in vitro and in a mouse model, and the results suggest that novobiocin is safe and effective for this use, indicating that the Hsp-90 family are potential drug targets.
Research Context
- The disease under focus in this research is equine piroplasmosis (EP), a blood disease affecting horses that is caused by Theileria equi and Babesia caballi parasites.
- The clinical form of EP is currently treated using imidocarb dipropionate (ID), but this drug has significant side effects and does not completely eliminate the infection.
- Therefore, alternative treatments are being explored, focusing on the role of heat-shock proteins (Hsp) in the life cycle of these parasites.
Role of Heat-shock Proteins
- Heat-shock proteins prevent alterations in protein conformation, which is crucial for the survival and transmission of parasites from the tick vector to the natural host.
- In this study, the researchers focused on heat shock protein 90 (Hsp-90) and tried to inhibit its pathway using the drug novobiocin.
Effect of Novobiocin
- The in vitro tests showed a dose-dependent efficacy of novobiocin on the growth of T. equi and B. caballi parasites.
- At certain concentrations of the drug, in vitro growth of parasites was significantly arrested, and the treated parasites showed no further viability.
- The researchers also examined the cytotoxicity of the drug on host peripheral mononuclear cells (PBMCs) and red blood cells (RBC), and found that it was safe even at high concentrations.
- In vivo organ toxicity of novobiocin was tested using a mouse model, and the results showed no adverse effects of the drug on the biochemical markers and the histopathology of the organs at the tested dosage.
Conclusions
- The results of the study suggest that novobiocin is effective in inhibiting the growth of T. equi and B. caballi parasites and is safe for use in host cells.
- The researchers concluded that Hsp-90 proteins are potential drug targets for the treatment of EP and that further investigation in this direction is warranted.
Cite This Article
APA
Suthar A, Maji C, Gopalkrishnan A, Raval SH, Kumar R, Kumar S.
(2021).
Anti-piroplasmic activity of novobiocin as heat shock protein 90 inhibitor against in vitro cultured Theileria equi and Babesia caballi parasites.
Ticks Tick Borne Dis, 12(4), 101696.
https://doi.org/10.1016/j.ttbdis.2021.101696 Publication
Researcher Affiliations
- ICAR - National Research Centre on Equines, Sirsa Road, Hisar, 125001, India; Division of Veterinary Medicine, Indian Veterinary Research Institute, Izatnagar, 243122, Uttar Pradesh, India; Department of Medicine, College of Veterinary Science & Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Dantiwada, 385506, Gujarat, India.
- ICAR - National Research Centre on Equines, Sirsa Road, Hisar, 125001, India; Subject matter specialist (Animal Health), North 24 Praganas Krishi Vigyan Kendra, WBUAFS, Ashokenagar, 743223, West Bengal, India.
- ICAR - National Research Centre on Equines, Sirsa Road, Hisar, 125001, India; Division of Veterinary Medicine, Indian Veterinary Research Institute, Izatnagar, 243122, Uttar Pradesh, India; Department of Veterinary Clinical Medicine, Madras Veterinary College, TANUVAS, Chennai, 600007, India.
- Department of Pathology, College of Veterinary Science & Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Dandiwada, 385506, Gujarat, India.
- ICAR - National Research Centre on Equines, Sirsa Road, Hisar, 125001, India.
- ICAR - National Research Centre on Equines, Sirsa Road, Hisar, 125001, India. Electronic address: sanjay.nrce@gmail.com.
MeSH Terms
- Antiprotozoal Agents / pharmacology
- Babesia / drug effects
- Babesia / genetics
- Babesia / growth & development
- HSP90 Heat-Shock Proteins / antagonists & inhibitors
- Novobiocin / pharmacology
- Theileria / drug effects
- Theileria / genetics
- Theileria / growth & development
Citations
This article has been cited 1 times.- Jenkins C, Micallef ML, Padula MP, Bogema DR. Characterisation of the Theileria orientalis Piroplasm Proteome across Three Common Genotypes.. Pathogens 2022 Sep 30;11(10).
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