Combination of buparvaquone and ELQ316 have a stronger syner-gistic effect than the combination of ELQ316 with imidocarb in in-hibiting Babesia bovis development in in vitro cultures

Authors: CARDILLO, NATALIA - Washington State University; VILLARINO, NICOLAS - Washington State University; Lacy, Paul; RISCOE, MICHAEL - Oregon Health & Science University; DOGGETT, STONE - Oregon Health & Science University; Ueti, Massaro; Chung, Chungwon; Suarez, Carlos

Submitted to: Pharmaceutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/29/2024
Publication Date: 10/31/2024
Citation: Cardillo, N.M., Villarino, N.F., Lacy, P.A., Riscoe, M.K., Doggett, S.J., Ueti, M.W., Chung, C.J., Suarez, C.E. 2024. Combination of buparvaquone and ELQ316 have a stronger syner-gistic effect than the combination of ELQ316 with imidocarb in in-hibiting Babesia bovis development in in vitro cultures. Pharmaceutics. 16(11):1402. https://doi.org/10.3390/pharmaceutics16111402.
DOI: https://doi.org/10.3390/pharmaceutics16111402

Interpretive Summary: Babesiosis, primarily caused by B. bovis and B. bigemina, is a tick-borne parasitic disease with significant impact on cattle industry worldwidely. Effective control of piroplasmosis includes three primary strategies: vaccination, the use of antipiroplasm drugs, and vector control measures. Most, if not all, of the more effective drugs currently in use have toxic side effects, release residues in the edible tissues of treated animals, or generate drug-resistant parasites. Overall, the findings in this study suggest that the combination treatment of BPQ and ELQ316 is a promising candidate for in vivo testing as a new babesiacidal regimen. ELQ316 highly improved BPQ performance killing the parasites faster at lower concentration doses than all the other drugs and combinations tested. This combination treatment is a promising option that may eliminate clinical B. bovis recrudescence and/or slow down drug resistance onset.

Technical Abstract: Bovine babesiosis is a vector-borne disease transmitted by ticks that causes important losses in livestock worldwide. Recent research performed on the drugs currently used to control bovine babesiosis reported several issues including drug resistance, toxicity impact, and residues in edible tissue, suggesting the need for developing novel effective therapies. The endochin-like quinolones ELQ-316 and buparvaquone (BPQ) act as cytochrome bc1 inhibitors and have been proven to be safe and efficacious against related apicomplexans, such as Plasmodium spp and Babesia microti, without showing toxicity in mammals. The objectives of this study are investigating whether ELQ-316, BPQ and their combination treatment could be effective against Babesia bovis in an in vitro culture model, and comparing their efficacy with Imidocarb (ID), the routinely used drug. Methods: In vitro cultured parasites at starting 2 % PPE were treated with BPQ, ELQ316, ID, and the combinations of BPQ+ELQ316 and ID+ELQ316 at drug concentrations that ranged from 25 to 1200 nM, during four consecutive days. Parasitemia levels were evaluated daily using microscopic examination. Data was compared using the independent Student's t-test and ANOVA test. Results: All drugs tested, whether used alone or in combination, significantly inhibited (p<0.05) the growth of B. bovis. The combination of BPQ+ELQ316 had the lowest