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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

Effect of ebselen on toxin production.Toxin production (ng/ml) in S. aureus MRSA USA300 after antibiotic/drug exposure for 1 hour corrected for organism burden. The results are given as means ± SD (n = 3). **indicate statistical significant different from control (DMSO or water). P values of (*P ≤ 0.05) (**P ≤ 0.01) are considered as significant. Detailed P values are listed: α Hemolysin: Control vs linezolid, 0.0144; Control vs ebselen, 0.0147. PVs-LK: Control vs linezolid, 0.0024; Control vs ebselen, 0.0288.
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f2: Effect of ebselen on toxin production.Toxin production (ng/ml) in S. aureus MRSA USA300 after antibiotic/drug exposure for 1 hour corrected for organism burden. The results are given as means ± SD (n = 3). **indicate statistical significant different from control (DMSO or water). P values of (*P ≤ 0.05) (**P ≤ 0.01) are considered as significant. Detailed P values are listed: α Hemolysin: Control vs linezolid, 0.0144; Control vs ebselen, 0.0147. PVs-LK: Control vs linezolid, 0.0024; Control vs ebselen, 0.0288.

Mentions: The effect of ebselen on production of important toxins such as Panton-Valentine leucocidin (PVL) and α-hemolysin (Hla) was tested by ELISA. The concentrations of each toxin were compared as unadjusted concentrations (ng/ml) and corrected for organism inoculum for each treatment (ng/ml to log10 colony-forming units, CFU/ml). Ebselen significantly suppressed toxin production in MRSA USA300 (Fig. 2).


Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections.

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

Effect of ebselen on toxin production.Toxin production (ng/ml) in S. aureus MRSA USA300 after antibiotic/drug exposure for 1 hour corrected for organism burden. The results are given as means ± SD (n = 3). **indicate statistical significant different from control (DMSO or water). P values of (*P ≤ 0.05) (**P ≤ 0.01) are considered as significant. Detailed P values are listed: α Hemolysin: Control vs linezolid, 0.0144; Control vs ebselen, 0.0147. PVs-LK: Control vs linezolid, 0.0024; Control vs ebselen, 0.0288.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Effect of ebselen on toxin production.Toxin production (ng/ml) in S. aureus MRSA USA300 after antibiotic/drug exposure for 1 hour corrected for organism burden. The results are given as means ± SD (n = 3). **indicate statistical significant different from control (DMSO or water). P values of (*P ≤ 0.05) (**P ≤ 0.01) are considered as significant. Detailed P values are listed: α Hemolysin: Control vs linezolid, 0.0144; Control vs ebselen, 0.0147. PVs-LK: Control vs linezolid, 0.0024; Control vs ebselen, 0.0288.
Mentions: The effect of ebselen on production of important toxins such as Panton-Valentine leucocidin (PVL) and α-hemolysin (Hla) was tested by ELISA. The concentrations of each toxin were compared as unadjusted concentrations (ng/ml) and corrected for organism inoculum for each treatment (ng/ml to log10 colony-forming units, CFU/ml). Ebselen significantly suppressed toxin production in MRSA USA300 (Fig. 2).

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