Topical Therapeutic Efficacy of Ebselen Against Multidrug-Resistant Staphylococcus aureus LT-1 Targeting Thioredoxin Reductase

Abstract

As a thiol-dependent enzyme, thioredoxin reductase (TrxR) is a promising antibacterial drug target. Ebselen, an organo-selenium with well-characterized toxicology and pharmacology, was recently reported to have potent antibacterial activity against <i>Staphylococcus aureus.</i> In this paper, we demonstrated that ebselen has strong bactericidal activity against multidrug-resistant (MDR) <i>S. aureus</i> based on taking TrxR as a major target and disruption of the redox microenvironment. Further, the topical therapeutic efficacy of ebselen for staphylococcal skin infections was assessed in a rat model. Treatment with ebselen significantly reduced the bacterial load and the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) in <i>S. aureus</i> skin lesions; further, wound healing and pathological changes were obvious improved in ebselen-treated rats compare to controls. Finally, ebselen was found to sensitize <i>S. aureus</i> to curcumin, which may be due to their synergistic effects in inhibiting bacterial TrxR. Altogether, ebselen is an effective topical antibacterial agent in animal model of MDR <i>S. aureus</i> LT-1 skin infection. This may lay the foundation for further analysis and development of ebselen as an antibacterial agent for topical treatment of MDR staphylococcal infections.