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

• Published in: Antimicrobial agents and chemotherapy 2021-08, Vol.65 (9), p.e0066221-e0066221
• Main Authors: Chiu, Joy E, Renard, Isaline, Pal, Anasuya C, Singh, Pallavi, Vydyam, Pratap, Thekkiniath, Jose, Kumar, Madelyn, Gihaz, Shalev, Pou, Sovitj, Winter, Rolf W, Dodean, Rozalia, Frueh, Lisa, Nilsen, Aaron C, Riscoe, Michael K, Doggett, J. Stone, Mamoun, Choukri Ben
• Format: Article
• Language: English
• Subjects: Experimental Therapeutics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00662-21

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 bc1 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 make it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.