Antivirulence activity of auranofin against vancomycin-resistant enterococci: in vitro and in vivo studies

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 Results: The present study determined that auranofin's antibacterial activity was not affected when evaluated against a higher inoculum size of VRE (similar to 10(7) 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. Conclusion: These results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.