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

Joseph Doggett, Aaron Nilsen, Isaac Forquer, Keith W. Wegmann, Lorraine Jones-Brando, Robert H. Yolken, Claudia Bordón, Susan A. Charman, Kasiram Katneni, Tracey Schultz, Jeremy N. Burrows, David J. Hinrichs, Brigitte Meunier, Vern B. Carruthers, Michael Riscoe

Research output: Contribution to journalArticle

75 Citations (Scopus)

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 bc 1 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.

Original languageEnglish (US)
Pages (from-to)15936-15941
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number39
DOIs
StatePublished - Sep 25 2012

Fingerprint

Toxoplasmosis
Quinolones
Toxoplasma
Qi
Electron Transport Complex III
Cysts
Central Nervous System Diseases
Amino Acid Substitution
Cytochromes
Inhibitory Concentration 50
Saccharomyces cerevisiae

Keywords

  • Antimalarial
  • Antiparasitic agents
  • Electron transport
  • Opportunistic infection
  • Quinoline

ASJC Scopus subject areas

  • General

Cite this

Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. / Doggett, Joseph; Nilsen, Aaron; Forquer, Isaac; Wegmann, Keith W.; Jones-Brando, Lorraine; Yolken, Robert H.; Bordón, Claudia; Charman, Susan A.; Katneni, Kasiram; Schultz, Tracey; Burrows, Jeremy N.; Hinrichs, David J.; Meunier, Brigitte; Carruthers, Vern B.; Riscoe, Michael.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 39, 25.09.2012, p. 15936-15941.

Research output: Contribution to journalArticle

Doggett, J, Nilsen, A, Forquer, I, Wegmann, KW, Jones-Brando, L, Yolken, RH, Bordón, C, Charman, SA, Katneni, K, Schultz, T, Burrows, JN, Hinrichs, DJ, Meunier, B, Carruthers, VB & Riscoe, M 2012, 'Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 39, pp. 15936-15941. https://doi.org/10.1073/pnas.1208069109
Doggett, Joseph ; Nilsen, Aaron ; Forquer, Isaac ; Wegmann, Keith W. ; Jones-Brando, Lorraine ; Yolken, Robert H. ; Bordón, Claudia ; Charman, Susan A. ; Katneni, Kasiram ; Schultz, Tracey ; Burrows, Jeremy N. ; Hinrichs, David J. ; Meunier, Brigitte ; Carruthers, Vern B. ; Riscoe, Michael. / Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 39. pp. 15936-15941.
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AU - Doggett, Joseph

AU - Nilsen, Aaron

AU - Forquer, Isaac

AU - Wegmann, Keith W.

AU - Jones-Brando, Lorraine

AU - Yolken, Robert H.

AU - Bordón, Claudia

AU - Charman, Susan A.

AU - Katneni, Kasiram

AU - Schultz, Tracey

AU - Burrows, Jeremy N.

AU - Hinrichs, David J.

AU - Meunier, Brigitte

AU - Carruthers, Vern B.

AU - Riscoe, Michael

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N2 - 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 bc 1 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.

AB - 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 bc 1 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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