TY - JOUR
T1 - Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone
AU - Lawres, Lauren A.
AU - Garg, Aprajita
AU - Kumar, Vidya
AU - Bruzual, Igor
AU - Forquer, Isaac P.
AU - Renard, Isaline
AU - Virji, Azan Z.
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.
AU - Hinrichs, David J.
AU - Riscoe, Michael K.
AU - Doggett, J. Stone
AU - Mamoun, Choukri Ben
N1 - Publisher Copyright:
© 2016 Lawres et al.
PY - 2016/6/27
Y1 - 2016/6/27
N2 - 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.
AB - 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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U2 - 10.1084/jem.20151519
DO - 10.1084/jem.20151519
M3 - Article
C2 - 27270894
AN - SCOPUS:84977632851
SN - 0022-1007
VL - 213
SP - 1307
EP - 1318
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -