title: Repurposing auranofin for the treatment of cutaneous staphylococcal infections.
abstract: The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug repurposing is a proven strategy to discover new antimicrobial agents; given that these agents have undergone extensive toxicological and pharmacological analysis, repurposing is an effective method to reduce the time, cost and risk associated with traditional antibiotic innovation. In this study, the in vitro and in vivo antibacterial activities of an antirheumatic drug, auranofin, was investigated against multidrug-resistant Staphylococcus aureus. The results indicated that auranofin possesses potent antibacterial activity against all tested strains of S. aureus, including meticillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 0.0625μg/mL to 0.125μg/mL. In vivo, topical auranofin proved superior to conventional antimicrobials, including fusidic acid and mupirocin, in reducing the mean bacterial load in infected wounds in a murine model of MRSA skin infection. In addition to reducing the bacterial load, topical treatment of auranofin greatly reduced the production of inflammatory cytokines, including tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), in infected skin lesions. Moreover, auranofin significantly disrupted established in vitro biofilms of S. aureus and Staphylococcus epidermidis, more so than the traditional antimicrobials linezolid and vancomycin. Taken together, these results support that auranofin has potential to be repurposed as a topical antimicrobial agent for the treatment of staphylococcal skin and wound 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; Department of Animal Hygiene and Zoonoses, 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: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA. Electronic address: mseleem@purdue.edu.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001310:Auranofin / Q000627:therapeutic use*; D018441:Biofilms / Q000187:drug effects; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D058492:Drug Repositioning; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D005672:Fusidic Acid / Q000627:therapeutic use; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D016712:Mupirocin / Q000627:therapeutic use; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000382:microbiology; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D001310:Auranofin; D005672:Fusidic Acid; D016712:Mupirocin
keywords: Auranofin; Inflammatory cytokines; Multidrug resistance; Repurposing; Topical antimicrobials