Cure of experimental babesiosis in immunodeficient mice using combination of endochin-like quinolone and atovaquone

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
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Martian
Posts: 1944
Joined: Thu 26 Jul 2007 18:29
Location: Friesland, the Netherlands

Cure of experimental babesiosis in immunodeficient mice using combination of endochin-like quinolone and atovaquone

Post by Martian » Thu 23 Jun 2016 16:02

Source: http://jem.rupress.org/content/early/20 ... m.20151519
PubMed: http://www.ncbi.nlm.nih.gov/pubmed/27270894
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.

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.

© 2016 Lawres et al.

PMID: 27270894 [PubMed - as supplied by publisher]

Martian
Posts: 1944
Joined: Thu 26 Jul 2007 18:29
Location: Friesland, the Netherlands

Re: Cure of experimental babesiosis in immunodeficient mice using combination of endochin-like quinolone and atovaquone

Post by Martian » Thu 23 Jun 2016 16:06

Source: http://news.yale.edu/2016/06/06/combina ... lness-mice
Combination therapy cures tick-borne illness in mice

By Ziba Kashef

June 6, 2016

A novel combination therapy cures an emerging infectious disease, babesiosis, which is transmitted by the same ticks that transmit the agents of Lyme disease, said Yale researchers. This “radical” therapy not only clears the infection but also prevents the recurrence that often occurs with existing treatments.

The study was published online June 6 in The Journal of Experimental Medicine.

Babesiosis (bab-e-see-oh-sis) is caused by the B. microti parasite, which is most often transmitted through tick bites. It is more common in the Northeast and northern Midwestern states, and likely is on the rise as infected ticks expand geographically. Infected individuals can be asymptomatic, or develop symptoms that range from mild and flu-like to severe and life threatening. The parasite can develop resistance to existing therapies, leading to relapses after treatment.

For their study, the Yale-led team first tested in mice with diminished immune systems four drugs that are currently used in the form of two combinations to treat human babesiosis. Only one of those drugs, atovaquone, was effective in attacking a target enzyme that, when mutated, allows the parasite to develop resistance. Using the mouse model, the team observed efficacy with a fifth drug (ELQ) that involves a similar mechanism of action as atovaquone but at a different enzyme target site. They decided to test the two drugs in combination.

The researchers found that the combination of atovaquone and ELQ-334, at low doses, cleared the infection and prevented recurrence up to 122 days after treatment.

“This is the first radical cure against this parasite,” said Choukri Ben Mamoun, associate professor of infectious diseases. “The novelty of the study was identifying a combination therapy that will both kill the parasite and also paralyze the target enzyme, making it nearly impossible for the parasite to develop resistance.”

The finding is significant since babesiosis is increasing and up to 19% of the ticks and up to 42% of the mammalian hosts (mice and other rodents) that carry the bacteria that cause Lyme disease is co-infected with B. microti.

With this finding, Ben Mamoun and his co-authors can take the next step and pursue studies of the combination therapy in people. “We are developing a better analog for ELQ that will be used in clinical trials. That’s what our future studies will focus on — identifying a better ELQ that could be added to atovaquone. We could test the safety of the compound in humans,” he said.

Other study authors include 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, and J. Stone Doggett.

The research was supported by the National Institutes of Health and the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development.

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