Limits...
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

Evaluation of toxicity and antimicrobial efficacy of EB in C. elegans model.(a) C. elegans strain glp-4; sek-1 (L4-stage) were grown for three days in the presence of EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml). Live worms were counted and the results were expressed as percent live worms in relative to the untreated control groups. (b) MRSA USA300 infected L4-stage worms were treated with EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml) for 24 h. Worms were lysed and the CFU were counted and the percent bacterial reduction per worm in treated groups were calculated in relative to the untreated control groups. P values of (** ≤ 0.05) are considered as significant.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4519285&req=5

pone.0133877.g005: Evaluation of toxicity and antimicrobial efficacy of EB in C. elegans model.(a) C. elegans strain glp-4; sek-1 (L4-stage) were grown for three days in the presence of EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml). Live worms were counted and the results were expressed as percent live worms in relative to the untreated control groups. (b) MRSA USA300 infected L4-stage worms were treated with EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml) for 24 h. Worms were lysed and the CFU were counted and the percent bacterial reduction per worm in treated groups were calculated in relative to the untreated control groups. P values of (** ≤ 0.05) are considered as significant.

Mentions: To investigate if the potent in vitro antimicrobial activity of EB translates to antimicrobial efficacy in vivo, we tested antimicrobial efficacy of EB in an infected C. elegans whole animal model. A whole animal model, such as C. elegans, represents a great platform for drug discovery and enables simultaneous assessment of efficacy and toxicity of the tested drugs. Additionally, using a C. elegans model reduces the associated cost of drug discovery and lowers the burden for extensive animal testing [13, 45]. Prior to testing the efficacy of treatment with EB in infected C. elegans, we tested toxicity of EB in non-infected C. elegans. As shown in Fig 5A, treatment of C. elegans with EB at 4 and 8 μg/ml for three days did not show any significant toxicity, similar to control groups. With no observable toxicity noticed in EB treated groups at a concentration of 4 and 8 μg/ml, we moved forward with an in vivo infection model using C. elegans infected with MRSA. As seen in Fig 5B, treatment with EB had a significant reduction in bacterial load when compared to untreated groups. EB at a concentration of 4 and 8 μg/ml significantly reduced the mean bacterial count by 56% and 85%, respectively. Moreover, treatment with EB at a concentration of 8 μg/ml showed comparable effect to treatment with the drug of choice vancomycin in reducing MRSA burden in infected C. elegans. Taken together, these results show that EB exhibits potent in vivo antistapylococcal efficacy in MRSA-infected C. elegans.


Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

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

Evaluation of toxicity and antimicrobial efficacy of EB in C. elegans model.(a) C. elegans strain glp-4; sek-1 (L4-stage) were grown for three days in the presence of EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml). Live worms were counted and the results were expressed as percent live worms in relative to the untreated control groups. (b) MRSA USA300 infected L4-stage worms were treated with EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml) for 24 h. Worms were lysed and the CFU were counted and the percent bacterial reduction per worm in treated groups were calculated in relative to the untreated control groups. 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.g005: Evaluation of toxicity and antimicrobial efficacy of EB in C. elegans model.(a) C. elegans strain glp-4; sek-1 (L4-stage) were grown for three days in the presence of EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml). Live worms were counted and the results were expressed as percent live worms in relative to the untreated control groups. (b) MRSA USA300 infected L4-stage worms were treated with EB (4μg and 8 μg/ml) and vancomycin (8 μg/ml) for 24 h. Worms were lysed and the CFU were counted and the percent bacterial reduction per worm in treated groups were calculated in relative to the untreated control groups. P values of (** ≤ 0.05) are considered as significant.
Mentions: To investigate if the potent in vitro antimicrobial activity of EB translates to antimicrobial efficacy in vivo, we tested antimicrobial efficacy of EB in an infected C. elegans whole animal model. A whole animal model, such as C. elegans, represents a great platform for drug discovery and enables simultaneous assessment of efficacy and toxicity of the tested drugs. Additionally, using a C. elegans model reduces the associated cost of drug discovery and lowers the burden for extensive animal testing [13, 45]. Prior to testing the efficacy of treatment with EB in infected C. elegans, we tested toxicity of EB in non-infected C. elegans. As shown in Fig 5A, treatment of C. elegans with EB at 4 and 8 μg/ml for three days did not show any significant toxicity, similar to control groups. With no observable toxicity noticed in EB treated groups at a concentration of 4 and 8 μg/ml, we moved forward with an in vivo infection model using C. elegans infected with MRSA. As seen in Fig 5B, treatment with EB had a significant reduction in bacterial load when compared to untreated groups. EB at a concentration of 4 and 8 μg/ml significantly reduced the mean bacterial count by 56% and 85%, respectively. Moreover, treatment with EB at a concentration of 8 μg/ml showed comparable effect to treatment with the drug of choice vancomycin in reducing MRSA burden in infected C. elegans. Taken together, these results show that EB exhibits potent in vivo antistapylococcal efficacy in MRSA-infected C. elegans.

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