Cure of experimental babesiosis in immunodeficient mice using combination of endochin-like quinolone and atovaquone
Posted: Thu 23 Jun 2016 16:02
Source: http://jem.rupress.org/content/early/20 ... m.20151519
J Exp Med. 2016 Jun 6. pii: jem.20151519. [Epub ahead of print]
Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone.
Lawres LA1, Garg A1, Kumar V1, Bruzual I2, Forquer IP2, Renard I1, Virji AZ1, Boulard P1, Rodriguez EX1, Allen AJ1, Pou S2, Wegmann KW2, Winter RW2, Nilsen A2, Mao J3, Preston DA2, Belperron AA3, Bockenstedt LK3, Hinrichs DJ2, Riscoe MK2, Doggett JS2, Ben Mamoun C4.
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.
PMID: 27270894 [PubMed - as supplied by publisher]