Antivirulence activity of auranofin against vancomycin-resistant enterococci: in vitro and in vivo studies |
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| Affiliation: | 1. Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA;2. Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, USA;1. Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain;2. Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain;3. Serviço de Microbiologia Centro Hospitalar Lisboa Norte, Lisboa, Portugal;4. Laboratório de Microbiologia, Serviço de Patologia Clínica, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal;5. Laboratório de Microbiologia Clínica Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal;6. Serviço de Microbiologia, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal;7. Serviço Patologia Clínica, Centro Hospitalar Universitário São João, Porto, Portugal;8. Serviço Patologia Clínica, Hospital Infante Dom Pedro, Aveiro, Portugal;9. Serviço de Patologia Clínica, Hospital Prof. Dr. Fernando da Fonseca, Amadora, Portugal;10. Serviço de Microbiologia, Hospital Garcia de Orta, Alnada, Portugal;11. Serviço de Patologia Clínica – Microbiologia – CHUA – Unidade de Portimão, Portimão, Portugal;12. Serviço de Microbiologia do Centro Hospitalar Universitário do Porto, Porto, Portugal;13. Serviço de Microbiologia, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal;14. MSD Portugal, Paço de Arcos, Portugal;1. Aix-Marseille Université, IRD, APHM, MEPHI, IHU Méditerranée Infection, Marseille, France;2. Aix-Marseille Université, IRD, SSA, APHM, VITROME, IHU Méditerranée Infection, Marseille, France;3. Département de cardiologie, Hôpital de la Timone, AP-HM, boulevard Jean-Moulin, 13005 Marseille, France;4. Laboratoire d''hématologie, Hôpital de la Timone, APHM, boulevard Jean Moulin, 13005 Marseille, France;1. Jawaharlal Nehru University, New Delhi 110067, India;2. National Centre for Disease Control, Delhi 110054, India;3. V.M. Govt. Medical College, Solapur, Maharashtra, India;4. SVN Govt. Medical College, Yavatmal, India;5. Defence Research and Development Establishment, Gwalior, India;6. Indian Institute of Science Education and Research (IISER), Berhampur, India;2. Department of Laboratory Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China;3. Department of Laboratory Medicine, Chongqing Dazu District People''s Hospital, Chongqing, China;4. Department of Clinical Laboratory, University of Chinese Academy of Sciences Chongqing Renji Hospital, Fifth People’s Hospital of Chongqing, Chongqing, China;5. Department of Laboratory Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China;1. London Research and Development Centre, Agriculture and Agri-Food Canada, London, Ontario, Canada;2. Ottawa Laboratory (Carling), Canadian Food Inspection Agency, Ottawa, Ontario, Canada;3. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada;4. Center for Structural Genomics of Infectious Diseases;5. Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada;6. Department of Biology, University of Western Ontario, London, Ontario, Canada;1. Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d''Ancona 20, 20127 Milan, Italy;2. Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy;3. University Hospital Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy |
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| Abstract: | Introduction: Vancomycin-resistant enterococci (VRE) are a leading cause of nosocomial infections because of the limited number of effective therapeutic options. In an effort to repurpose FDA-approved drugs against antibiotic-resistant bacteria, auranofin has been identified as a potent drug against VRE.Methods and ResultsThe present study determined that auranofin's antibacterial activity was not affected when evaluated against a higher inoculum size of VRE (~107 CFU/mL), and auranofin successfully reduced the burden of stationary phase VRE cells via a time-kill assay. In addition, auranofin reduced VRE production of key virulence factors, including proteases, lipase and haemagglutinin. The promising features of auranofin prompted evaluation of its in vivo efficacy in a lethal mouse model of VRE septicaemia. All mice receiving auranofin at 0.125 mg/kg orally, 0.125 mg/kg subcutaneously (SC) or 0.0625 mg/kg (SC) survived the lethal VRE challenge. Additionally, auranofin was superior to linezolid, the current drug of choice, in reducing VRE burden in the liver, kidneys and spleen of mice. Remarkably, auranofin successfully reduced VRE below the limit of detection in murine internal organs after 4 days of oral or subcutaneous treatment.ConclusionThese results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections. |
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