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. 2024 Apr 12;10(4):1405-1413.
doi: 10.1021/acsinfecdis.4c00143. Epub 2024 Apr 2.

Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis

Pratap Vydyam, Meenal Chand, Sovitj Pou  1 , Rolf W Winter  1 , Katherine M Liebman  1 , Aaron Nilsen  1   2 , J Stone Doggett  1   3 , Michael K Riscoe  1   4 , Choukri Ben Mamoun
Affiliations

Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis

Pratap Vydyam et al. ACS Infect Dis. .

Abstract

Endochin-like quinolones (ELQs) define a class of small molecule antimicrobials that target the mitochondrial electron transport chain of various human parasites by inhibiting their cytochrome bc1 complexes. The compounds have shown potent activity against a wide range of protozoan parasites, including the intraerythrocytic parasites Plasmodium and Babesia, the agents of human malaria and babesiosis, respectively. First-generation ELQ compounds were previously found to reduce infection by Babesia microti and Babesia duncani in animal models of human babesiosis but achieved a radical cure only in combination with atovaquone and required further optimization to address pharmacological limitations. Here, we report the identification of two second-generation 3-biaryl ELQ compounds, ELQ-596 and ELQ-650, with potent antibabesial activity in vitro and favorable pharmacological properties. In particular, ELQ-598, a prodrug of ELQ-596, demonstrated high efficacy as an orally administered monotherapy at 10 mg/kg. The compound achieved radical cure in both the chronic model of B. microti-induced babesiosis in immunocompromised mice and the lethal infection model induced by B. duncani in immunocompetent mice. Given its high potency, favorable physicochemical properties, and low toxicity profile, ELQ-596 represents a promising drug for the treatment of human babesiosis.

Keywords: B. duncani; B. microti; Babesia; ELQ-596; endochin-like quinolones; human babesiosis; parasite.

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Conflict of interest statement

Conflict of Interest Statement

Choukri Ben Mamoun, Pratap Vydyam and Meenal Chand declare no conflict of interest. Sovitj Pou, Rolf W. Winter, Katherine M. Liebman, Aaron Nilsen, J. Stone Doggett, Michael K. Riscoe are listed as co-inventors of technology that is involved in this research and which has been licensed by OHSU for commercial development. This potential conflict of interest has been reviewed and managed by OHSU and the Portland VAMC.

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