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

Autor:	Lawres LA; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Garg A; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Kumar V; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Bruzual I; Veterans Affairs Medical Center, Portland, OR 97239., Forquer IP; Veterans Affairs Medical Center, Portland, OR 97239., Renard I; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Virji AZ; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Boulard P; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Rodriguez EX; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Allen AJ; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520., Pou S; Veterans Affairs Medical Center, Portland, OR 97239., Wegmann KW; Veterans Affairs Medical Center, Portland, OR 97239., Winter RW; Veterans Affairs Medical Center, Portland, OR 97239., Nilsen A; Veterans Affairs Medical Center, Portland, OR 97239., Mao J; Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520., Preston DA; Veterans Affairs Medical Center, Portland, OR 97239., Belperron AA; Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520., Bockenstedt LK; Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520., Hinrichs DJ; Veterans Affairs Medical Center, Portland, OR 97239., Riscoe MK; Veterans Affairs Medical Center, Portland, OR 97239., Doggett JS; Veterans Affairs Medical Center, Portland, OR 97239., Ben Mamoun C; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520 choukri.benmamoun@yale.edu.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2016 Jun 27; Vol. 213 (7), pp. 1307-18. Date of Electronic Publication: 2016 Jun 06.
DOI:	10.1084/jem.20151519
Abstrakt:	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. (© 2016 Lawres et al.)
Databáze:	MEDLINE
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