Characterization of cytochrome b from Toxoplasma gondii and Qo domain mutations as a mechanism of atovaquone-resistance

McFadden, Diane C.; Tomavo, Stanislas; Berry, Edward A.; Boothroyd, John C.

doi:10.1016/s0166-6851(00)00184-5

Cited by 155 publications

(132 citation statements)

References 41 publications

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“…The resulting modeled structure accounted for the enzymatic and spectroscopic results and was more stable than the structure lacking the water-mediated hydrogen bond. This computed structure differs significantly from two previously postulated structures for atovaquone bound to the bc 1 complex (12,13). In those structures, the hydroxyl group of atovaquone was oriented toward Glu 272 in both cases, and one of the structures failed to account for atovaquone interaction with the Rieske protein (13).…”

Section: Discussioncontrasting

confidence: 85%

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Kessl

Lange

Merbitz-Zahradnik

et al. 2003

Journal of Biological Chemistry

154

163

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Atovaquone is a substituted 2-hydroxynaphthoquinone that is used therapeutically to treat Plasmodium falciparum malaria, Pneumocystis carinii pneumonia, and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting the cytochrome bc 1 complex. We have examined the interaction of atovaquone with the bc 1 complex isolated from Saccharomyces cerevisiae, a surrogate, nonpathogenic fungus. Atovaquone inhibits the bc 1 complex competitively with apparent K i ‫؍‬ 9 nM, raises the midpoint potential of the Rieske iron-sulfur protein from 285 to 385 mV, and shifts the g values in the EPR spectrum of the Rieske center. These results indicate that atovaquone binds to the ubiquinol oxidation pocket of the bc 1 complex, where it interacts with the Rieske iron-sulfur protein. A computed energy-minimized structure for atovaquone liganded to the yeast bc 1 complex suggests that a phenylalanine at position 275 of cytochrome b in the bovine bc 1 complex, as opposed to leucine at the equivalent position in the yeast enzyme, is responsible for the decreased sensitivity of the bovine bc 1 complex (K i ‫؍‬ 80 nM) to atovaquone. When a L275F mutation was introduced into the yeast cytochrome b, the sensitivity of the yeast enzyme to atovaquone decreased (K i ‫؍‬ 100 nM) with no loss in activity, confirming that the L275F exchange contributes to the differential sensitivity of these two species to atovaquone. These results provide the first molecular description of how atovaquone binds to the bc 1 complex and explain the differential inhibition of the fungal versus mammalian enzymes.

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Section: Discussioncontrasting

confidence: 85%

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Kessl

Lange

Merbitz-Zahradnik

et al. 2003

Journal of Biological Chemistry

154

163

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“…This has been demonstrated for T. gondii (84) and P. carinii, which has recently been reclassified from a parasite to a fungus (124). In Pneumocystis, inhibition of ubiquinone binding results in inhibition of DHOD (61) and markedly decreased levels of ATP (26).…”

Section: Mechanism Of Actionmentioning

confidence: 88%

Antiparasitic Agent Atovaquone

Baggish

Hill

2002

Antimicrob Agents Chemother

213

147

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“…This drug is a structural analog of Coenzyme Q, inhibiting bc1 cytochrome activity as it binds to its Q domain. In a study carried out by McFadden et al (2000), alterations in this domain have been identified to likely lead to resistance to atovaquone. Thus, further studies aiming at determining alterations in studied strains, which may offer resistance to the tested drugs, are needed.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of atovaquone and sulfadiazine in the treatment of mice infected withToxoplasma gondiistrains isolated in Brazil

Alves

Vítor

2005

Parasite

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Summary :The efficacy of atovaquone and sulfadiazine was examined alone or in combination for the treatment of mice infected with six Brazilian Toxoplasma gondii strains previously genotyped using the PCR-RFLP assays of the SAG2 gene, in addition to RH strain. Swiss mice were infected intraperitoneally with 10 2 tachyzoites from each strain of T. gondii and treated with 6.25, 12.5, 25 and 50 mg/Kg/day of atovaquone or 40, 80, 160 and 320 mg/Kg/day of sulfadiazine. In a second experiment, mice were treated with the association of previously determined doses of each drug. Treatment started 48 hours post-infection, and lasted 10 days. The susceptibility of T. gondii to atovaquone and to sulfadiazine was different according to the parasite strain. It was observed strains that are susceptible to atovaquone, and strains that are resistant to it. Type I strains were more susceptible to the activity of sulfadiazine and more resistant to atovaquone. Yet type III strains were susceptible to atovaquone and to sulfadiazine. Association of atovaquone and sulfadiazine presented a synergic effect in the treatment of mice infected with RH type I strain and an additive effect in the treatment of mice infected with one type I strain and with two type III strains. Résumé

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Characterization of cytochrome b from Toxoplasma gondii and Qo domain mutations as a mechanism of atovaquone-resistance

Cited by 155 publications

References 41 publications

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Antiparasitic Agent Atovaquone

Efficacy of atovaquone and sulfadiazine in the treatment of mice infected withToxoplasma gondiistrains isolated in Brazil

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