Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection

Chiu, J. E.; Renard, I.; Chattopadhyay Pal, A.; Singh, P.; Vydyam, P.; Thekkiniath, J.; Kumar, M.; Gihaz, S.; Pou, S.; Winter, R. W.; Dodean, R.; Nilsen, A.; Riscoe, M. K.; Doggett, J. S.; Ben Mamoun, C.

doi:10.1101/2021.03.31.438003

bioRxiv · 10.1101/2021.03.31.438003

Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection

Chiu, J. E.·Renard, I.·Chattopadhyay Pal, A.·Singh, P.·Vydyam, P.·Thekkiniath, J.·Kumar, M.·Gihaz, S.·Pou, S.·Winter, R. W.·Dodean, R.·Nilsen, A.·Riscoe, M. K.·Doggett, J. S.·Ben Mamoun, C.

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Abstract

Targeting conserved metabolic processes that are essential for viability of pathogens, such as Plasmodium and Babesia that cause blood-borne diseases, is an effective strategy to eliminate malaria and babesiosis infections with no recrudescence. One interesting target is the mitochondrial cytochrome bc1 complex, which could be inhibited by drugs such as endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen Babesia duncani to evaluate the structure-activity relationship, safety, efficacy and mode of action of ELQs. We identified a potent and highly selective ELQ prodrug (ELQ-502), which alone or in combination with atovaquone eliminates B. microti and B. duncani infections in vitro and in mouse models of parasitemia and lethal infection. The strong efficacy at low dose, excellent safety, bioavailability and long half-life of this experimental therapy makes it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.

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Chiu, J. E., Renard, I., Chattopadhyay Pal, A., Singh, P., Vydyam, P., Thekkiniath, J., Kumar, M., Gihaz, S., Pou, S., Winter, R. W., Dodean, R., Nilsen, A., Riscoe, M. K., Doggett, J. S., Ben Mamoun, C.. 2021-04-01. Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection. https://doi.org/10.1101/2021.03.31.438003

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