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

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 and , the infectious agents of malaria and babesiosis, respectively, is the mitochondrial cytochrom...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2021-08, Vol.65 (9), p.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:
Animals
Atovaquone - pharmacology
Babesia
Babesiosis - drug therapy
Babesiosis - prevention & control
Cytochromes
Mice
Parasitemia - drug therapy
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Summary: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 and , the infectious agents of malaria and babesiosis, respectively, is the mitochondrial cytochrome protein complex, which can be inhibited by endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen 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 infections 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 and its closely related apicomplexan parasites.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00662-21