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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

The effects of ebselen and antibiotics (linezolid, mupirocin, vancomycin and rifampicin) on established biofilms of S. aureus (a) or S. epidermidis(b).The established biofilms were treated with control antibiotics or ebselen and stained with crystal violet. Optical density of dissolved crystal violet was measured using a spectrophotometer. Values are the mean of triplicate samples with the standard deviation bars. P values of (*,#P ≤ 0.05) are considered as significant. Ebselen was compared to controls (*) and to antibiotics (#). Detailed P values are listed: S. aureus (a): Control vs linezolid, 0.0214; Control vs mupirocin, 0.0001; Control vs vancomycin, 0.004; Control vs rifampicin, 0.0001; Control vs ebselen, 0.0001; linezolid vs ebselen, 0.0014; mupirocin vs ebselen, 0.0004; vancomycin vs ebselen, 0.003; rifampicin vs ebselen, 0.0047. S. epidermidis (b): Control vs linezolid, 0.0036; Control vs mupirocin, 0.0008; Control vs vancomycin, 0.0011; Control vs rifampicin, 0.0004; Control vs ebselen, 0.0004; linezolid vs ebselen, 0.0033; mupirocin vs ebselen, 0.0052; vancomycin vs ebselen, 0.0040; rifampicin vs ebselen, n.s (not significant).
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f3: The effects of ebselen and antibiotics (linezolid, mupirocin, vancomycin and rifampicin) on established biofilms of S. aureus (a) or S. epidermidis(b).The established biofilms were treated with control antibiotics or ebselen and stained with crystal violet. Optical density of dissolved crystal violet was measured using a spectrophotometer. Values are the mean of triplicate samples with the standard deviation bars. P values of (*,#P ≤ 0.05) are considered as significant. Ebselen was compared to controls (*) and to antibiotics (#). Detailed P values are listed: S. aureus (a): Control vs linezolid, 0.0214; Control vs mupirocin, 0.0001; Control vs vancomycin, 0.004; Control vs rifampicin, 0.0001; Control vs ebselen, 0.0001; linezolid vs ebselen, 0.0014; mupirocin vs ebselen, 0.0004; vancomycin vs ebselen, 0.003; rifampicin vs ebselen, 0.0047. S. epidermidis (b): Control vs linezolid, 0.0036; Control vs mupirocin, 0.0008; Control vs vancomycin, 0.0011; Control vs rifampicin, 0.0004; Control vs ebselen, 0.0004; linezolid vs ebselen, 0.0033; mupirocin vs ebselen, 0.0052; vancomycin vs ebselen, 0.0040; rifampicin vs ebselen, n.s (not significant).

Mentions: Considering the excellent broad-spectrum activity of ebselen against the MRSA and VRSA strains, we also considered the possibility that ebselen would be active against established biofilm. Biofilm-forming strains of S. aureus and S. epidermidis were used and the biofilm mass was estimated after treatment with ebselen and control antibiotics. Ebselen was significantly superior in reducing adherent biofilms of both S. aureus and S. epidermidis when compared to conventional antibiotics (linezolid, mupirocin, vancomycin and rifampicin). Ebselen at (2 μg/ml)(16X MIC) significantly reduced the biofilm mass, approximately by 60%. Control antibiotics, such as linezolid (256 μg/ml) (128X MIC), mupirocin (16 μg/ml) (128X MIC), and vancomycin (128 μg/ml) (128X MIC), were able to reduce the biofilm mass only by 20%. Rifampicin at 0.5 μg/ml (16X MIC) reduced the biofilm mass by only 40% (Fig. 3a).


Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections.

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

The effects of ebselen and antibiotics (linezolid, mupirocin, vancomycin and rifampicin) on established biofilms of S. aureus (a) or S. epidermidis(b).The established biofilms were treated with control antibiotics or ebselen and stained with crystal violet. Optical density of dissolved crystal violet was measured using a spectrophotometer. Values are the mean of triplicate samples with the standard deviation bars. P values of (*,#P ≤ 0.05) are considered as significant. Ebselen was compared to controls (*) and to antibiotics (#). Detailed P values are listed: S. aureus (a): Control vs linezolid, 0.0214; Control vs mupirocin, 0.0001; Control vs vancomycin, 0.004; Control vs rifampicin, 0.0001; Control vs ebselen, 0.0001; linezolid vs ebselen, 0.0014; mupirocin vs ebselen, 0.0004; vancomycin vs ebselen, 0.003; rifampicin vs ebselen, 0.0047. S. epidermidis (b): Control vs linezolid, 0.0036; Control vs mupirocin, 0.0008; Control vs vancomycin, 0.0011; Control vs rifampicin, 0.0004; Control vs ebselen, 0.0004; linezolid vs ebselen, 0.0033; mupirocin vs ebselen, 0.0052; vancomycin vs ebselen, 0.0040; rifampicin vs ebselen, n.s (not significant).
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Related In: Results  -  Collection

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Show All Figures
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f3: The effects of ebselen and antibiotics (linezolid, mupirocin, vancomycin and rifampicin) on established biofilms of S. aureus (a) or S. epidermidis(b).The established biofilms were treated with control antibiotics or ebselen and stained with crystal violet. Optical density of dissolved crystal violet was measured using a spectrophotometer. Values are the mean of triplicate samples with the standard deviation bars. P values of (*,#P ≤ 0.05) are considered as significant. Ebselen was compared to controls (*) and to antibiotics (#). Detailed P values are listed: S. aureus (a): Control vs linezolid, 0.0214; Control vs mupirocin, 0.0001; Control vs vancomycin, 0.004; Control vs rifampicin, 0.0001; Control vs ebselen, 0.0001; linezolid vs ebselen, 0.0014; mupirocin vs ebselen, 0.0004; vancomycin vs ebselen, 0.003; rifampicin vs ebselen, 0.0047. S. epidermidis (b): Control vs linezolid, 0.0036; Control vs mupirocin, 0.0008; Control vs vancomycin, 0.0011; Control vs rifampicin, 0.0004; Control vs ebselen, 0.0004; linezolid vs ebselen, 0.0033; mupirocin vs ebselen, 0.0052; vancomycin vs ebselen, 0.0040; rifampicin vs ebselen, n.s (not significant).
Mentions: Considering the excellent broad-spectrum activity of ebselen against the MRSA and VRSA strains, we also considered the possibility that ebselen would be active against established biofilm. Biofilm-forming strains of S. aureus and S. epidermidis were used and the biofilm mass was estimated after treatment with ebselen and control antibiotics. Ebselen was significantly superior in reducing adherent biofilms of both S. aureus and S. epidermidis when compared to conventional antibiotics (linezolid, mupirocin, vancomycin and rifampicin). Ebselen at (2 μg/ml)(16X MIC) significantly reduced the biofilm mass, approximately by 60%. Control antibiotics, such as linezolid (256 μg/ml) (128X MIC), mupirocin (16 μg/ml) (128X MIC), and vancomycin (128 μg/ml) (128X MIC), were able to reduce the biofilm mass only by 20%. Rifampicin at 0.5 μg/ml (16X MIC) reduced the biofilm mass by only 40% (Fig. 3a).

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