title: Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens.
abstract: Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin's antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin's ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections.
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Thangamani
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: Haroon
authors.initials: H
authors.lastname: Mohammad
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.|Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
authors.forename: Mostafa F N
authors.initials: MF
authors.lastname: Abushahba
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
authors.forename: Tiago J P
authors.initials: TJ
authors.lastname: Sobreira
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Hedrick
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
authors.forename: Lake N
authors.initials: LN
authors.lastname: Paul
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
mesh_terms: D000818:Animals; D001310:Auranofin / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000378:metabolism*; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects*; D013203:Staphylococcal Infections / Q000188:drug therapy*
chemical_list: D001426:Bacterial Proteins; D001310:Auranofin