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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

Activity of EB, vancomycin and linezolid against intracellular MRSA USA300 in J774A.1 cells.MRSA infected J774A.1 cells were treated with EB and control antibiotics (vancomycin and linezolid) for 24 h and the percent bacterial reduction was calculated compared to untreated control groups. The results are given as means ± SD (n = 3). P values of (**, # ≤ 0.05) are considered as significant. EB was compared to controls (**) and to antibiotics (#).
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pone.0133877.g001: Activity of EB, vancomycin and linezolid against intracellular MRSA USA300 in J774A.1 cells.MRSA infected J774A.1 cells were treated with EB and control antibiotics (vancomycin and linezolid) for 24 h and the percent bacterial reduction was calculated compared to untreated control groups. The results are given as means ± SD (n = 3). P values of (**, # ≤ 0.05) are considered as significant. EB was compared to controls (**) and to antibiotics (#).

Mentions: Some extracellular pathogens such as S. aureus are also capable of invading and surviving within the mammalian host cells, leading to persistent chronic infections. Moreover, during the S. aureus intracellular invasion phase, treatment with antimicrobials is very challenging because most antibiotics do not actively pass through cellular membranes [20–27]. Therefore, clinical failures of drug of choice, such as vancomycin, to cure S. aureus pneumonia have exceeded 40% and have been attributed mainly to poor intracellular penetration of the drug and consequently to the failure to kill intracellular MRSA in alveolar macrophages [28]. Hence, finding antimicrobials that possess both extra- and intracellular activity would be an optimum strategy to treat such invasive intracellular S. aureus infections. Therefore, we investigated if EB possesses intracellular anti-staphylococcal activity. As shown in Fig 1, EB at a concentration of 1 μg/ml significantly reduced the intracellular MRSA by 32%. In contrast, the conventional antimicrobials such as vancomycin and linezolid (drugs of choice for treatment of MRSA infections) at the same concentration reduced intracellular MRSA by only 16% and 21%, respectively. EB toxicity was assayed against J774A.1 cells at a concentration ranging from 0 to 256 μg/ml for 24 h. The results shown in Fig 2 indicate that EB does not show toxicity up to 64 μg/ml. The concentration of the EB that causes 50% toxicity (half inhibitory concentration: IC50) in J774A.1 cells is 95.68 ± 4.12 μg/ml. This value is more than 380-fold higher than the concentration required to inhibit MRSA. Collectively, these results suggest that EB has great potential for treatment of S. aureus infections where not only is eradication of extracellular bacteria important, but the killing of intracellular bacteria is also critical [29].


Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

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

Activity of EB, vancomycin and linezolid against intracellular MRSA USA300 in J774A.1 cells.MRSA infected J774A.1 cells were treated with EB and control antibiotics (vancomycin and linezolid) for 24 h and the percent bacterial reduction was calculated compared to untreated control groups. The results are given as means ± SD (n = 3). P values of (**, # ≤ 0.05) are considered as significant. EB was compared to controls (**) and to antibiotics (#).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133877.g001: Activity of EB, vancomycin and linezolid against intracellular MRSA USA300 in J774A.1 cells.MRSA infected J774A.1 cells were treated with EB and control antibiotics (vancomycin and linezolid) for 24 h and the percent bacterial reduction was calculated compared to untreated control groups. The results are given as means ± SD (n = 3). P values of (**, # ≤ 0.05) are considered as significant. EB was compared to controls (**) and to antibiotics (#).
Mentions: Some extracellular pathogens such as S. aureus are also capable of invading and surviving within the mammalian host cells, leading to persistent chronic infections. Moreover, during the S. aureus intracellular invasion phase, treatment with antimicrobials is very challenging because most antibiotics do not actively pass through cellular membranes [20–27]. Therefore, clinical failures of drug of choice, such as vancomycin, to cure S. aureus pneumonia have exceeded 40% and have been attributed mainly to poor intracellular penetration of the drug and consequently to the failure to kill intracellular MRSA in alveolar macrophages [28]. Hence, finding antimicrobials that possess both extra- and intracellular activity would be an optimum strategy to treat such invasive intracellular S. aureus infections. Therefore, we investigated if EB possesses intracellular anti-staphylococcal activity. As shown in Fig 1, EB at a concentration of 1 μg/ml significantly reduced the intracellular MRSA by 32%. In contrast, the conventional antimicrobials such as vancomycin and linezolid (drugs of choice for treatment of MRSA infections) at the same concentration reduced intracellular MRSA by only 16% and 21%, respectively. EB toxicity was assayed against J774A.1 cells at a concentration ranging from 0 to 256 μg/ml for 24 h. The results shown in Fig 2 indicate that EB does not show toxicity up to 64 μg/ml. The concentration of the EB that causes 50% toxicity (half inhibitory concentration: IC50) in J774A.1 cells is 95.68 ± 4.12 μg/ml. This value is more than 380-fold higher than the concentration required to inhibit MRSA. Collectively, these results suggest that EB has great potential for treatment of S. aureus infections where not only is eradication of extracellular bacteria important, but the killing of intracellular bacteria is also critical [29].

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