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

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.

• Authors: 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 K Riscoe, J Stone Doggett, Choukri Ben Mamoun
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 213 Issue 7 Pg. 1307-18 (06 27 2016) ISSN: 1540-9538 [Electronic] United States
• PMID: 27270894 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2016 Lawres et al.

Chemical References

• Prodrugs
• Quinolones
• Atovaquone

Topics

• Animals
• Atovaquone (pharmacology)
• Babesia microti (immunology)
• Babesiosis (drug therapy, genetics, immunology)
• Immunologic Deficiency Syndromes (genetics, immunology, parasitology)
• Mice
• Mice, SCID
• Prodrugs (pharmacology)
• Quinolones (pharmacology)