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J Exp Med. 2016 Jun 27;213(7):1307-18. doi: 10.1084/jem.20151519. Epub 2016 Jun 6.

Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone.

Author information

1
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
2
Veterans Affairs Medical Center, Portland, OR 97239.
3
Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520.
4
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520 choukri.benmamoun@yale.edu.

Abstract

Human babesiosis is a tick-borne multisystem disease caused by Babesia species of the apicomplexan phylum. Most clinical cases and fatalities of babesiosis are caused by Babesia microti Current treatment for human babesiosis consists of two drug combinations, atovaquone + azithromycin or quinine + clindamycin. These treatments are associated with adverse side effects and a significant rate of drug failure. Here, we provide evidence for radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone (ELQ) prodrug and atovaquone. In vivo efficacy studies in mice using ELQ-271, ELQ-316, and the ELQ-316 prodrug, ELQ-334, demonstrated excellent growth inhibitory activity against the parasite, with potency equal to that of orally administered atovaquone at 10 mg/kg. Analysis of recrudescent parasites after ELQ or atovaquone monotherapy identified genetic substitutions in the Qi or Qo sites, respectively, of the cytochrome bc1 complex. Impressively, a combination of ELQ-334 and atovaquone, at doses as low as 5.0 mg/kg each, resulted in complete clearance of the parasite with no recrudescence up to 122 d after discontinuation of therapy. These results will set the stage for future clinical evaluation of ELQ and atovaquone combination therapy for treatment of human babesiosis.

PMID:
27270894
PMCID:
PMC4925016
DOI:
10.1084/jem.20151519
[Indexed for MEDLINE]
Free PMC Article

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