Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections

Sci Rep. 2015 Jun 26;5:11596. doi: 10.1038/srep11596.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Azoles / pharmacology*
  • Bacterial Toxins / metabolism
  • Biofilms / drug effects
  • Biofilms / growth & development
  • Cell Survival / drug effects
  • Cells, Cultured
  • Daptomycin / pharmacology
  • Drug Repositioning
  • Drug Synergism
  • Female
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Keratinocytes / drug effects
  • Methicillin Resistance / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / metabolism
  • Methicillin-Resistant Staphylococcus aureus / physiology
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mupirocin / pharmacology
  • Organoselenium Compounds / pharmacology*
  • Skin / drug effects
  • Skin / metabolism
  • Skin / microbiology
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology

Substances

  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Azoles
  • Bacterial Toxins
  • Organoselenium Compounds
  • ebselen
  • Mupirocin
  • Daptomycin