title: Auranofin inactivates Trichomonas vaginalis thioredoxin reductase and is effective against trichomonads in vitro and in vivo.
abstract: Trichomoniasis, caused by the protozoan parasite Trichomonas vaginalis, is the most common, non-viral, sexually transmitted infection in the world, but only two closely related nitro drugs are approved for its treatment. New antimicrobials against trichomoniasis remain an urgent need. Several organic gold compounds were tested for activity against T. vaginalis thioredoxin reductase (TrxR) in cell-free systems as well as for activity against different trichomonads in vitro and in a murine infection model. The organic gold(I) compounds auranofin and chloro(diethylphenylphosphine)gold(I) inhibited TrxR in a concentration-dependent manner in assays with recombinant purified reductase and in cytoplasmic extracts of T. vaginalis transfected with a haemagglutinin epitope-tagged form of the reductase. Auranofin potently suppressed the growth of three independent clinical T. vaginalis isolates as well as several strains of another trichomonad (Tritrichomonas foetus) in a 24 h-assay, with 50% inhibitory concentrations of 0.7-2.5 µM and minimum lethal concentrations of 2-6 µM. The drug also compromised the ability of the parasite to overcome oxidant stress, supporting the notion that auranofin acts, in part, by inactivating TrxR-dependent antioxidant defences. Chloro(diethylphenylphosphine)gold(I) was 10-fold less effective against T. vaginalis in vitro than auranofin. Oral administration of auranofin for 4 days cleared the parasites in a murine model of vaginal T. foetus infection without displaying any apparent adverse effects. The approved human drug auranofin may be a promising agent as an alternative treatment of trichomoniasis in cases when standard nitro drug therapies have failed.
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hopper
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Jeong-Fil
authors.initials: JF
authors.lastname: Yun
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Bianhua
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Le
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Katelin
authors.initials: K
authors.lastname: Kehoe
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Le
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hill
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Gregg
authors.initials: G
authors.lastname: Jongeward
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Anjan
authors.initials: A
authors.lastname: Debnath
authors.affiliation: Department of NanoEngineering, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: leckmann@ucsd.edu.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Kirkwood M
authors.initials: KM
authors.lastname: Land
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Wrischnik
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020128:Inhibitory Concentration 50; D008810:Mice, Inbred C57BL; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014247:Trichomonas Vaginitis / Q000188:drug therapy* / Q000469:parasitology; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D016835:Tritrichomonas foetus / Q000187:drug effects / Q000254:growth & development
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase
keywords: Antimicrobial therapy; Auranofin; Drug development; Gold compounds; Parasite; Protozoa