Effective therapy targeting cytochrome bc1prevents babesia erythrocytic development and protects from lethal infection

Joy E. Chiu, Isaline Renard, Anasuya C. Pal, Pallavi Singh, Pratap Vydyam, Jose Thekkiniath, Madelyn Kumar, Shalev Gihaz, Sovitj Pou, Rolf W. Winter, Rozalia Dodean, Lisa Frueh, Aaron C. Nilsen, Michael K. Riscoe, J. Stone Doggett, Choukri Ben Mamoun

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 bc1protein 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.

Original languageEnglish (US)
Article numbere00662-21
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number9
DOIs
StatePublished - Sep 2021
Externally publishedYes

Keywords

  • Apicomplexan parasites
  • Babesia duncani
  • Babesia microti
  • Babesiosis
  • Endochin-like quinolone
  • Parasitology
  • Red blood cells
  • Therapy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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