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

Lauren A. Lawres, Aprajita Garg, Vidya Kumar, Igor Bruzual, Isaac P. Forquer, Isaline Renard, Azan Z. Virji, Pierre Boulard, Eduardo X. Rodriguez, Alexander J. Allen, Sovitj Pou, Keith W. Wegmann, Rolf W. Winter, Aaron Nilsen, Jialing Mao, Douglas A. Preston, Alexia A. Belperron, Linda K. Bockenstedt, David J. Hinrichs, Michael Riscoe & 2 others Joseph Doggett, Choukri Ben Mamoun

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1307-1318
Number of pages12
JournalJournal of Experimental Medicine
Volume213
Issue number7
DOIs
StatePublished - 2016

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Atovaquone
Babesiosis
Quinolones
Parasites
Prodrugs
Babesia microti
Tick-Borne Diseases
Qi
Babesia
Therapeutics
Azithromycin
Quinine
Clindamycin
Electron Transport Complex III
Drug Combinations
Recurrence

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone. / Lawres, Lauren A.; Garg, Aprajita; Kumar, Vidya; Bruzual, Igor; Forquer, Isaac P.; Renard, Isaline; Virji, Azan Z.; Boulard, Pierre; Rodriguez, Eduardo X.; Allen, Alexander J.; Pou, Sovitj; Wegmann, Keith W.; Winter, Rolf W.; Nilsen, Aaron; Mao, Jialing; Preston, Douglas A.; Belperron, Alexia A.; Bockenstedt, Linda K.; Hinrichs, David J.; Riscoe, Michael; Doggett, Joseph; Mamoun, Choukri Ben.

In: Journal of Experimental Medicine, Vol. 213, No. 7, 2016, p. 1307-1318.

Research output: Contribution to journalArticle

Lawres, LA, Garg, A, Kumar, V, Bruzual, I, Forquer, IP, Renard, I, Virji, AZ, Boulard, P, Rodriguez, EX, Allen, AJ, Pou, S, Wegmann, KW, Winter, RW, Nilsen, A, Mao, J, Preston, DA, Belperron, AA, Bockenstedt, LK, Hinrichs, DJ, Riscoe, M, Doggett, J & Mamoun, CB 2016, 'Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone', Journal of Experimental Medicine, vol. 213, no. 7, pp. 1307-1318. https://doi.org/10.1084/jem.20151519
Lawres, Lauren A. ; Garg, Aprajita ; Kumar, Vidya ; Bruzual, Igor ; Forquer, Isaac P. ; Renard, Isaline ; Virji, Azan Z. ; Boulard, Pierre ; Rodriguez, Eduardo X. ; Allen, Alexander J. ; Pou, Sovitj ; Wegmann, Keith W. ; Winter, Rolf W. ; Nilsen, Aaron ; Mao, Jialing ; Preston, Douglas A. ; Belperron, Alexia A. ; Bockenstedt, Linda K. ; Hinrichs, David J. ; Riscoe, Michael ; Doggett, Joseph ; Mamoun, Choukri Ben. / Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone. In: Journal of Experimental Medicine. 2016 ; Vol. 213, No. 7. pp. 1307-1318.
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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.",
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AU - Forquer, Isaac P.

AU - Renard, Isaline

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AU - Boulard, Pierre

AU - Rodriguez, Eduardo X.

AU - Allen, Alexander J.

AU - Pou, Sovitj

AU - Wegmann, Keith W.

AU - Winter, Rolf W.

AU - Nilsen, Aaron

AU - Mao, Jialing

AU - Preston, Douglas A.

AU - Belperron, Alexia A.

AU - Bockenstedt, Linda K.

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AU - Riscoe, Michael

AU - Doggett, Joseph

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