Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections

Abstract

Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections.

Repurposing auranofin for the treatment of cutaneous staphylococcal infections

“…All animal procedures were approved by the Purdue University Animal Care and Use Committee (West Lafayette, IN). An in vivo murine MRSA skin infection study was conducted as described elsewhere [2,22–24]. Briefly, mice (five mice per group) received an intradermal injection (40 μL) of MRSA USA300 containing 1.65 × 10 8 CFU.…”

“…The ability of auranofin to disrupt adherent staphylococcal biofilm was analysed using the microtitre dish biofilm formation assay [2,27]. Staphylococcus aureus ATCC 6538 and Staphylococcus epidermidis ATCC 35984 were inoculated in TSB supplemented with 1% glucose and were transferred to the wells of a 96-well tissue culture treated plate (CELLTREAT Scientific, Shirley, MA).…”

“…Furthermore, cutaneous staphylococcal skin infections can develop into invasive infections that ultimately result in septicaemia [5,6]. Recently, skin infections with biofilm-producing staphylococci have become an emerging clinical problem; treatment failure is occurring more frequently with the topical drugs of choice, including mupirocin and fusidic acid, indicating that new treatment options are urgently required [2,7,8]. The recent US Food and Drug Administration (FDA) approval of drugs such as tedizolid phosphate and dalbavancin to combat skin infections caused by Gram-positive pathogens [9,10] further highlights the pressing need for the identification of new antibacterials capable of treating cutaneous meticillin-resistant S. aureus (MRSA) infections.…”

“…Recently, we assembled and screened one-half of all commercially available drugs (ca. 2200 drugs) and small molecules used in human clinical trials [2,12] and identified three drugs (auranofin, ebselen and 5-fluoro-2'-deoxyuridine) [2,13,14] that exhibited potent antibacterial activity against important clinical pathogens. One of these drugs, auranofin, was found to inhibit the growth of clinical isolates of MRSA at submicrogram/mL concentrations in vitro.…”

Development of ebsulfur analogues as potent antibacterials against methicillin-resistant Staphylococcus aureus

“…19 Finally, ebselen especially caught our attention because it demonstrated potent bactericidal activity against many clinical isolates of drug-resistant S. aureus and was effective in a murine model of MRSA skin infection. 20 These findings prompted us to investigate the antibacterial activity of our own library of ebselen-inspired compounds.…”