Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone.
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.
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Lauren A
LA
Lawres
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Aprajita
A
Garg
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Vidya
V
Kumar
Veterans Affairs Medical Center, Portland, OR 97239.
Igor
I
Bruzual
Veterans Affairs Medical Center, Portland, OR 97239.
Isaac P
IP
Forquer
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Isaline
I
Renard
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Azan Z
AZ
Virji
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Pierre
P
Boulard
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Eduardo X
EX
Rodriguez
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520.
Alexander J
AJ
Allen
Veterans Affairs Medical Center, Portland, OR 97239.
Sovitj
S
Pou
Veterans Affairs Medical Center, Portland, OR 97239.
Keith W
KW
Wegmann
Veterans Affairs Medical Center, Portland, OR 97239.
Rolf W
RW
Winter
Veterans Affairs Medical Center, Portland, OR 97239.
Aaron
A
Nilsen
Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520.
Jialing
J
Mao
Veterans Affairs Medical Center, Portland, OR 97239.
Douglas A
DA
Preston
Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520.
Alexia A
AA
Belperron
Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520.
Linda K
LK
Bockenstedt
Veterans Affairs Medical Center, Portland, OR 97239.
David J
DJ
Hinrichs
Veterans Affairs Medical Center, Portland, OR 97239.
Michael K
MK
Riscoe
Veterans Affairs Medical Center, Portland, OR 97239.
J Stone
JS
Doggett
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520 choukri.benmamoun@yale.edu.
Choukri
C
Ben Mamoun
D000818:Animals; D053626:Atovaquone / Q000494:pharmacology*; D041001:Babesia microti / Q000276:immunology*; D001404:Babesiosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000469:parasitology*; D051379:Mice; D016513:Mice, SCID; D011355:Prodrugs / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*
D011355:Prodrugs; D015363:Quinolones; D053626:Atovaquone