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Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

Thangamani S, Younis W, Seleem MN - PLoS ONE (2015)

Bottom Line: One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug.Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid.Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, United States of America.

ABSTRACT
Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

No MeSH data available.


Related in: MedlinePlus

Effects of EB on coupled transcription-translation (TT) in S30 extracts from E. coli.(a) Average luciferin protein production in the presence of EB, ampicillin and chloramphenicol at the concentration of 2 μg/ml were shown. The results are given as means ± SD (n = 3). (b) Concentration dependent TT-inhibition of EB and chloramphenicol were shown. IC50 of the drugs required to inhibit 50% TT-activity were determined. P values of (** ≤ 0.05) are considered as significant.
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pone.0133877.g003: Effects of EB on coupled transcription-translation (TT) in S30 extracts from E. coli.(a) Average luciferin protein production in the presence of EB, ampicillin and chloramphenicol at the concentration of 2 μg/ml were shown. The results are given as means ± SD (n = 3). (b) Concentration dependent TT-inhibition of EB and chloramphenicol were shown. IC50 of the drugs required to inhibit 50% TT-activity were determined. P values of (** ≤ 0.05) are considered as significant.

Mentions: Antimicrobials that target microbial protein synthesis such as oxazolidinones and lincomycins are considered excellent choices for the treatment of toxin-mediated bacterial infections caused by S. aureus, such as toxic shock syndrome (TSS) and pneumonia [30–33]. In addition to the suppression of S. aureus toxins such as Panton-Valentine leucocidin (PVL), α-hemolysin (hla), and toxic shock syndrome toxin–1 (TSST-1), these antimicrobials also reduce excessive host-inflammatory responses associated with these toxins [34, 35]. Hence, protein synthesis inhibitors are often preferred in clinical practice for the treatment of toxin-associated staphylococcal infections [30–33]. We tested the effects of EB in our study on bacterial, mammalian and mitochondrial protein-synthesis. For bacterial protein-synthesis inhibition, we used E. coli cellular extracts in a transcription and translation assay that monitors protein production via luciferase readout. Unlike the antibiotic ampicillin that inhibits cell wall synthesis, EB strongly inhibited bacterial transcription/translation process similar to chloramphenicol antibiotic that inhibits protein synthesis (Fig 3A). EB inhibited bacterial protein synthesis in the cell-free transcription-translation, exhibiting IC50 of 0.25±0.10 μg/ml which is comparable to IC50 of chloramphenicol antibiotic 0.48 ± 0.10 μg/ml (Fig 3B). These results indicate that EB acts by a favorable mechanism of action and inhibits bacterial protein synthesis and, most likely, toxin production. However, inhibition of bacterial protein synthesis does not exclude other possible mechanism of action of EB.


Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

Thangamani S, Younis W, Seleem MN - PLoS ONE (2015)

Effects of EB on coupled transcription-translation (TT) in S30 extracts from E. coli.(a) Average luciferin protein production in the presence of EB, ampicillin and chloramphenicol at the concentration of 2 μg/ml were shown. The results are given as means ± SD (n = 3). (b) Concentration dependent TT-inhibition of EB and chloramphenicol were shown. IC50 of the drugs required to inhibit 50% TT-activity were determined. P values of (** ≤ 0.05) are considered as significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519285&req=5

pone.0133877.g003: Effects of EB on coupled transcription-translation (TT) in S30 extracts from E. coli.(a) Average luciferin protein production in the presence of EB, ampicillin and chloramphenicol at the concentration of 2 μg/ml were shown. The results are given as means ± SD (n = 3). (b) Concentration dependent TT-inhibition of EB and chloramphenicol were shown. IC50 of the drugs required to inhibit 50% TT-activity were determined. P values of (** ≤ 0.05) are considered as significant.
Mentions: Antimicrobials that target microbial protein synthesis such as oxazolidinones and lincomycins are considered excellent choices for the treatment of toxin-mediated bacterial infections caused by S. aureus, such as toxic shock syndrome (TSS) and pneumonia [30–33]. In addition to the suppression of S. aureus toxins such as Panton-Valentine leucocidin (PVL), α-hemolysin (hla), and toxic shock syndrome toxin–1 (TSST-1), these antimicrobials also reduce excessive host-inflammatory responses associated with these toxins [34, 35]. Hence, protein synthesis inhibitors are often preferred in clinical practice for the treatment of toxin-associated staphylococcal infections [30–33]. We tested the effects of EB in our study on bacterial, mammalian and mitochondrial protein-synthesis. For bacterial protein-synthesis inhibition, we used E. coli cellular extracts in a transcription and translation assay that monitors protein production via luciferase readout. Unlike the antibiotic ampicillin that inhibits cell wall synthesis, EB strongly inhibited bacterial transcription/translation process similar to chloramphenicol antibiotic that inhibits protein synthesis (Fig 3A). EB inhibited bacterial protein synthesis in the cell-free transcription-translation, exhibiting IC50 of 0.25±0.10 μg/ml which is comparable to IC50 of chloramphenicol antibiotic 0.48 ± 0.10 μg/ml (Fig 3B). These results indicate that EB acts by a favorable mechanism of action and inhibits bacterial protein synthesis and, most likely, toxin production. However, inhibition of bacterial protein synthesis does not exclude other possible mechanism of action of EB.

Bottom Line: One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug.Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid.Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, United States of America.

ABSTRACT
Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

No MeSH data available.


Related in: MedlinePlus