Article

Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis

Division of Infectious Diseases and Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2012; 109(39):15936-15941. DOI: 10.1073/pnas.1208069109

ABSTRACT

Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that
the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC50 values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED50 values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316
are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76–88% after 16 d of treatment. To investigate the ELQ mechanism of action
against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bc1 complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome bc1 complex, and an M221Q amino acid substitution in the Qi site of the protein leads to >100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that
are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Qi site of the T. gondii cytochrome bc1 complex.

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