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. 2017 Jan 24;61(2):e01866-16.
doi: 10.1128/AAC.01866-16. Print 2017 Feb.

Genetic Evidence for Cytochrome b Qi Site Inhibition by 4(1H)-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

P Holland Alday  1 , Igor Bruzual  2 , Aaron Nilsen  2 , Sovitj Pou  2 , Rolf Winter  2 , Choukri Ben Mamoun  3 , Michael K Riscoe  2 , J Stone Doggett  4   2
Affiliations

Genetic Evidence for Cytochrome b Qi Site Inhibition by 4(1H)-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii

P Holland Alday et al. Antimicrob Agents Chemother. .

Abstract

Toxoplasma gondii is an apicomplexan parasite that causes fatal and debilitating brain and eye disease. Endochinlike quinolones (ELQs) are preclinical compounds that are efficacious against apicomplexan-caused diseases, including toxoplasmosis, malaria, and babesiosis. Of the ELQs, ELQ-316 has demonstrated the greatest efficacy against acute and chronic experimental toxoplasmosis. Although genetic analyses in other organisms have highlighted the importance of the cytochrome bc1 complex Qi site for ELQ sensitivity, the mechanism of action of ELQs against T. gondii and the specific mechanism of ELQ-316 remain unknown. Here, we describe the selection and genetic characterization of T. gondii clones resistant to ELQ-316. A T. gondii strain selected under ELQ-316 drug pressure was found to possess a Thr222-Pro amino acid substitution that confers 49-fold resistance to ELQ-316 and 19-fold resistance to antimycin, a well-characterized Qi site inhibitor. These findings provide further evidence for ELQ Qi site inhibition in T. gondii and greater insight into the interactions of Qi site inhibitors with the apicomplexan cytochrome bc1 complex.

Keywords: Toxoplasma gondii; apicomplexan parasites; cytochrome b; cytochrome bc1; drug targets; experimental therapeutics; mechanisms of action; mitochondria; parasitology; preclinical drug studies.

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Figures

FIG 1
FIG 1
Chemical structures of cytochrome bc1 inhibitors. ELQ, endochinlike quinolone.
FIG 2
FIG 2
Cytochrome b protein sequence alignment. (A) Qi site, α-helix E protein sequence alignment between wild-type T. gondii, T. gondii strain ER1, Plasmodium falciparum, Saccharomyces cerevisiae, and human (Homo sapiens) cytochrome b. The Thr222-Pro substitution is in boldface. (B) Putative T. gondii cytochrome b N terminus.
FIG 3
FIG 3
Resistance to cytochrome bc1 inhibitors. Strain ER1, which possesses a Thr222-Pro substitution, is resistant to Qi site inhibitors but not atovaquone compared to the resistances of the parental strain. *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; n.s., not significant; error bars show standard deviations.
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