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Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: 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.

Author information

1
Division of Infectious Diseases, Oregon Health & Science University, Portland, Oregon, USA.
2
Department of Research and Development, Portland VA Medical Center, Portland, Oregon, USA.
3
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
4
Division of Infectious Diseases, Oregon Health & Science University, Portland, Oregon, USA doggettj@ohsu.edu.

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

PMID:
27919897
PMCID:
PMC5278733
DOI:
10.1128/AAC.01866-16
[Indexed for MEDLINE]
Free PMC Article

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