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Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections.

Thangamani S, Younis W, Seleem MN - Sci Rep (2015)

Bottom Line: Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Macromolecular synthesis in the presence of ebselen.Incorporation of radiolabeled precursors of DNA, RNA, protein, cell wall and lipid synthesis ([3H] thymidine, [3H] uridine, [3H] leucine, [14C] N-acetylglucosamine and [3H] glycerol, respectively) were quantified in S. aureus ATCC 29213. Results were expressed as percent of inhibition calculated based on the incorporation of radiolabeled precursors.
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f1: Macromolecular synthesis in the presence of ebselen.Incorporation of radiolabeled precursors of DNA, RNA, protein, cell wall and lipid synthesis ([3H] thymidine, [3H] uridine, [3H] leucine, [14C] N-acetylglucosamine and [3H] glycerol, respectively) were quantified in S. aureus ATCC 29213. Results were expressed as percent of inhibition calculated based on the incorporation of radiolabeled precursors.

Mentions: Given the potent anti-staphylococcal activity of ebselen in vitro, we investigated its anti-staphylococcal mechanism of action by macromolecular synthesis assay. As shown in Fig. 1, ebselen primarily inhibited protein synthesis at 1X the MIC. However, additional secondary effects were observed at a higher concentration (8X MIC). At higher concentration, ebselen inhibited DNA, RNA and lipid synthesis similar to control antibiotics such as ciprofloxacin, rifampicin and cerulenin respectively.


Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections.

Thangamani S, Younis W, Seleem MN - Sci Rep (2015)

Macromolecular synthesis in the presence of ebselen.Incorporation of radiolabeled precursors of DNA, RNA, protein, cell wall and lipid synthesis ([3H] thymidine, [3H] uridine, [3H] leucine, [14C] N-acetylglucosamine and [3H] glycerol, respectively) were quantified in S. aureus ATCC 29213. Results were expressed as percent of inhibition calculated based on the incorporation of radiolabeled precursors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481386&req=5

f1: Macromolecular synthesis in the presence of ebselen.Incorporation of radiolabeled precursors of DNA, RNA, protein, cell wall and lipid synthesis ([3H] thymidine, [3H] uridine, [3H] leucine, [14C] N-acetylglucosamine and [3H] glycerol, respectively) were quantified in S. aureus ATCC 29213. Results were expressed as percent of inhibition calculated based on the incorporation of radiolabeled precursors.
Mentions: Given the potent anti-staphylococcal activity of ebselen in vitro, we investigated its anti-staphylococcal mechanism of action by macromolecular synthesis assay. As shown in Fig. 1, ebselen primarily inhibited protein synthesis at 1X the MIC. However, additional secondary effects were observed at a higher concentration (8X MIC). At higher concentration, ebselen inhibited DNA, RNA and lipid synthesis similar to control antibiotics such as ciprofloxacin, rifampicin and cerulenin respectively.

Bottom Line: Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.

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.

No MeSH data available.


Related in: MedlinePlus