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Antivirulence activity of auranofin against vancomycin-resistant enterococci: in vitro and in vivo studies
Nader S Abutaleb1, Mohamed N Seleem2
1Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA.
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 (~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.
Conclusion:
These results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections.
Insights
Auranofin shows potent activity against vancomycin-resistant enterococci (VRE), reducing bacterial burden and virulence factors. This repurposed drug offers a promising new treatment for VRE infections, outperforming current therapies in mouse models.
Area of Science:
- Infectious Diseases
- Pharmacology
- Microbiology
Background:
- Vancomycin-resistant enterococci (VRE) are a significant cause of hospital-acquired infections.
- Limited therapeutic options exist for VRE infections.
- Auranofin, an FDA-approved drug, has emerged as a potential agent against VRE.
Purpose of the Study:
- To evaluate the efficacy of auranofin against VRE.
- To assess auranofin's impact on VRE virulence factors.
- To determine auranofin's in vivo effectiveness in a VRE sepsis mouse model.
Main Methods:
- Time-kill assays were used to assess auranofin's antibacterial activity against VRE at high inoculum.
- VRE virulence factor production was measured in the presence of auranofin.
- In vivo efficacy was tested in a lethal mouse model of VRE septicaemia, comparing auranofin to linezolid.
Main Results:
- Auranofin demonstrated potent antibacterial activity against VRE, unaffected by high inoculum.
- Auranofin reduced VRE virulence factors, including proteases, lipase, and haemagglutinin.
- In vivo, auranofin treatment led to complete survival in mice with VRE septicaemia and was superior to linezolid in reducing bacterial burden in organs.
Conclusions:
- Auranofin exhibits significant potential as a novel therapeutic agent for systemic VRE infections.
- Further investigation into auranofin for VRE treatment is warranted.
- Auranofin's efficacy in reducing bacterial load and virulence factors highlights its therapeutic promise.
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