Effective Therapy Targeting Cytochrome bc ₁ Prevents Babesia Erythrocytic Development and Protects from Lethal Infection

Abstract

An effective strategy to control blood-borne diseases and prevent outbreak recrudescence involves targeting conserved metabolic processes that are essential for pathogen viability. One such target for Plasmodium and Babesia, the infectious agents of malaria and babesiosis, respectively, is the mitochondrial cytochrome bc 1 protein complex, which can be inhibited by 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.

Treatment of Human Babesiosis: Then and Now

“…In a lethal model of B. microti infection in hamsters, atovaquone monotherapy was found to be superior to a combination of clindamycin + quinine, resulting in low to undetectable parasitemia and extended survival [58]. Potency of atovaquone was also demonstrated in B. divergens [59] and B. duncani [57] models, with IC 50 values in the low nanomolar range. In gerbils, although prophylaxis experiments were not successful, a dose of atovaquone as low as 0.5 mg/kg was found to efficiently prevent B. divergens infection, so long as daily treatment was maintained several days post-infection [59].…”

“…Continuous in vitro culture system in hamster [77,78] and human [79] RBCs Mice [57,82,83], hamsters [80,81] Overall, there is a wide variety of Babesia models available. However, finding complementary systems can prove challenging.…”

“…ELQ-502 was assessed in B. duncaniand B. microti-infected mice as a single drug (10 mg/kg) and in combination with atovaquone (10 + 10 mg/kg). Following a 10-day treatment course, both the mono-and the combination therapies resulted in radical cure with no recrudescence, and in the case of B. duncani-infected mice, 100% survival [57]. Interestingly, a shorter treatment duration with ELQ-502 alone at 10 mg/kg in B. microti-infected mice resulted in recrudescence [109].…”

“…Similar results were obtained in B. microti -infected hamsters, where 150 mg/kg azithromycin treatment regimen, administered daily for almost two weeks, showed no apparent effect on parasitemia [ 56 ]. Out of the four clinically used drugs in the treatment of babesiosis, only atovaquone seems to consistently show high potency against Babesia parasites [ 11 , 56 , 57 , 58 , 59 ]. Studies carried out in B. microti -infected hamsters and SCID mice reported fast clearance of parasitemia following treatment with atovaquone [ 11 , 56 ].…”

“…In gerbils, although prophylaxis experiments were not successful, a dose of atovaquone as low as 0.5 mg/kg was found to efficiently prevent B. divergens infection, so long as daily treatment was maintained several days post-infection [ 59 ]. In the case of B. duncani , a treatment course of 10 mg/kg atovaquone resulted in a clear reduction of parasitemia and 80% survival using a mouse model of lethal infection [ 57 ]. The results derived from the evaluation of atovaquone, azithromycin, clindamycin, and quinine in preclinical models of babesiosis are summarized in Table 1 .…”