title: Auranofin is highly efficacious against Toxoplasma gondii in vitro and in an in vivo experimental model of acute toxoplasmosis.
abstract: BACKGROUND
  The mainstay of toxoplasmosis treatment targets the folate biosynthetic pathways and has not changed for the last 50 years. The activity of these chemotherapeutic agents is restricted to one lifecycle stage of Toxoplasma gondii, they have significant toxicity, and the impending threat of emerging resistance to these agents makes the discovery of new therapies a priority. We now demonstrate that auranofin, an orally administered gold containing compound that was FDA approved for treatment of rheumatoid arthritis, has activity against Toxoplasma gondii in vitro (IC50 = 0.28 µM) and in vivo (1 mg/kg).
  
  
  RESULTS
  Replication within human foreskin fibroblasts of RH tachyzoites was inhibited by auranofin. At 0.4 µM, auranofin inhibited replication, as measured by percent infected fibroblasts at 24 hrs, (10.94% vs. 24.66% of controls; p = 0.0003) with no effect on parasite invasion (16.95% vs. 12.91% p = 0.4331). After 18 hrs, 62% of extracellular parasites treated with auranofin were non-viable compared to control using an ATP viability assay (p = 0.0003). In vivo, a previously standardized chicken embryo model of acute toxoplasmosis was used. Fourteen day old chicken embryos were injected through the chorioallantoic vein with 1×104 tachyzoites of the virulent RH strain. The treatment group received one dose of auranofin at the time of inoculation (1 mg/kg estimated body weight). On day 5, auranofin-treated chicken embryos were 100% protected against death (p = 0.0002) and had a significantly reduced parasite load as determined by histopathology, immunohistochemistry and by the number of parasites quantified by real-time PCR.
  
  
  CONCLUSIONS
  These results reveal in vitro and in vivo activity of auranofin against T. gondii, suggesting that it may be an effective alternative treatment for toxoplasmosis.
authors: Department of Medicine, University of California, San Diego, San Diego, California, United States of America.
authors: Rosa M
authors: RM
authors: Andrade
authors: Department of Pediatrics, University of California, San Diego, San Diego, California, United States of America.
authors: Juan D
authors: JD
authors: Chaparro
authors: Department of Pediatrics, University of California, San Diego, San Diego, California, United States of America.
authors: Edmund
authors: E
authors: Capparelli
authors: Department of Medicine, University of California, San Diego, San Diego, California, United States of America; Department of Pathology, University of California, San Diego, San Diego, California, United States of America.
authors: Sharon L
authors: SL
authors: Reed
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001310:Auranofin / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004195:Disease Models, Animal; D058492:Drug Repositioning; D005347:Fibroblasts / Q000469:parasitology; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D059208:Parasite Load; D021261:Parasitic Sensitivity Tests; D060888:Real-Time Polymerase Chain Reaction; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D014123:Toxoplasmosis / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D001310:Auranofin