title: Genetic Evidence for Cytochrome b Qi Site Inhibition by 4(1H)-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii.
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 bc1complex Qisite 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 Qisite inhibitor. These findings provide further evidence for ELQ Qisite inhibition in T. gondii and greater insight into the interactions of Qisite inhibitors with the apicomplexan cytochrome bc1complex.
authors.affiliation: Division of Infectious Diseases, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: P Holland
authors.initials: PH
authors.lastname: Alday
authors.affiliation: Department of Research and Development, Portland VA Medical Center, Portland, Oregon, USA.
authors.forename: Igor
authors.identifier: 0000-0003-4155-7596
authors.initials: I
authors.lastname: Bruzual
authors.affiliation: Department of Research and Development, Portland VA Medical Center, Portland, Oregon, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Nilsen
authors.affiliation: Department of Research and Development, Portland VA Medical Center, Portland, Oregon, USA.
authors.forename: Sovitj
authors.initials: S
authors.lastname: Pou
authors.affiliation: Department of Research and Development, Portland VA Medical Center, Portland, Oregon, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Winter
authors.affiliation: Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Choukri
authors.initials: C
authors.lastname: Ben Mamoun
authors.affiliation: Department of Research and Development, Portland VA Medical Center, Portland, Oregon, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Riscoe
authors.affiliation: Division of Infectious Diseases, Oregon Health & Science University, Portland, Oregon, USA doggettj@ohsu.edu.|Department of Research and Development, Portland VA Medical Center, Portland, Oregon, USA.
authors.forename: J Stone
authors.initials: JS
authors.lastname: Doggett
mesh_terms: D000968:Antimycin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D045303:Cytochromes b / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects* / Q000378:metabolism; D014123:Toxoplasmosis / Q000469:parasitology
chemical_list: D015363:Quinolones; C032456:antimycin; D000968:Antimycin A; D045303:Cytochromes b
keywords: Toxoplasma gondii; apicomplexan parasites; cytochrome b; cytochrome bc1; drug targets; experimental therapeutics; mechanisms of action; mitochondria; parasitology; preclinical drug studies