title: Auranofin efficacy against MDR Streptococcus pneumoniae and Staphylococcus aureus infections.
abstract: BACKGROUND
  Auranofin is an FDA-approved, gold-containing compound in clinical use for the oral treatment of rheumatoid arthritis and has been recently granted by the regulatory authorities due to its antiprotozoal properties.
  
  
  METHODS
  A reprofiling strategy was performed with a Streptococcus pneumoniae phenotypic screen and a proprietary library of compounds, consisting of both FDA-approved and unapproved bioactive compounds. Two different multiresistant S. pneumoniae strains were employed in a sepsis mouse model of infection. In addition, an MRSA strain was tested using both the thigh model and a mesh-associated biofilm infection in mice.
  
  
  RESULTS
  The repurposing approach showed the high potency of auranofin against multiresistant clinical isolates of S. pneumoniae and Staphylococcus aureus in vitro and in vivo. Efficacy in the S. pneumoniae sepsis model was obtained using auranofin by the oral route in the dose ranges used for the treatment of rheumatoid arthritis. Thioglucose replacement by alkyl chains showed that this moiety was not essential for the antibacterial activity and led to the discovery of a new gold derivative (MH05) with remarkable activity in vitro and in vivo.
  
  
  CONCLUSIONS
  Auranofin and the new gold derivative MH05 showed encouraging in vivo activity against multiresistant clinical isolates of S. pneumoniae and S. aureus. The clinical management of auranofin, alone or in combination with other antibiotics, deserves further exploration before use in patients presenting therapeutic failure caused by infections with multiresistant Gram-positive pathogens. Decades of clinical use mean that this compound is safe to use and may accelerate its evaluation in humans.
authors.affiliation: Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain Department of Bacteriology, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Aguinagalde
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Díez-Martínez
authors.affiliation: Department of Bacteriology, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Yuste
authors.affiliation: Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Royo
authors.affiliation: Instituto de Agrobiología, Universidad Pública de Navarra, CSIC, Campus de Arrosadía, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.affiliation: Instituto de Agrobiología, Universidad Pública de Navarra, CSIC, Campus de Arrosadía, Pamplona, Spain.
authors.forename: Íñigo
authors.initials: Í
authors.lastname: Lasa
authors.affiliation: Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.affiliation: Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain CEI Campus Moncloa, UCM-UPM and CSIC, Madrid, Spain.
authors.forename: Nagore Isabel
authors.initials: NI
authors.lastname: Marín-Ramos
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Department of Microbiology, Hospital Universitari de Bellvitge - IDIBELL - Universitat de Barcelona, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ardanuy
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Department of Microbiology, Hospital Universitari de Bellvitge - IDIBELL - Universitat de Barcelona, Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Liñares
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: García
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
authors.forename: Ernesto
authors.initials: E
authors.lastname: García
authors.affiliation: Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain jm.spuelles@csic.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Sánchez-Puelles
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001310:Auranofin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013290:Streptococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D001310:Auranofin