title: Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis.
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 IC(50) values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED(50) 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 bc(1) complex, and an M221Q amino acid substitution in the Q(i) 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 Q(i) site of the T. gondii cytochrome bc(1) complex.
authors.affiliation: Division of Infectious Diseases, Oregon Health and Science University, Portland, OR 97239, USA. doggettj@ohsu.edu
authors.forename: J Stone
authors.initials: JS
authors.lastname: Doggett
authors.forename: Aaron
authors.initials: A
authors.lastname: Nilsen
authors.forename: Isaac
authors.initials: I
authors.lastname: Forquer
authors.forename: Keith W
authors.initials: KW
authors.lastname: Wegmann
authors.forename: Lorraine
authors.initials: L
authors.lastname: Jones-Brando
authors.forename: Robert H
authors.initials: RH
authors.lastname: Yolken
authors.forename: Claudia
authors.initials: C
authors.lastname: Bordón
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Tracey
authors.initials: T
authors.lastname: Schultz
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: David J
authors.initials: DJ
authors.lastname: Hinrichs
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunier
authors.forename: Vern B
authors.initials: VB
authors.lastname: Carruthers
authors.forename: Michael K
authors.initials: MK
authors.lastname: Riscoe
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors; D014122:Toxoplasma / Q000201:enzymology / Q000254:growth & development*; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011804:Quinolines; D029701:Saccharomyces cerevisiae Proteins; D014450:Electron Transport Complex III