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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

Synergistic activities of EB with conventional antibiotics in vitro and in cell culture.(a) The Bliss Model for Synergy confirms the in vitro synergism with conventional antimicrobials (gentamicin, rifampicin, erythromycin, chloramphenicol, vancomycin, clindamycin and linezolid) against MRSA USA300. Degree of synergy was calculated in the presence of EB (0.0312 μg/ml) in combination with sub-inhibitory concentrations of conventional antimicrobials. (b) Synergistic activity of EB with conventional antimicrobials in infected cell culture. Efficacy of EB (0.5μg/ml) in combination with linezolid (4μg/ml), clindamycin (1μg/ml), vancomycin (4μg/ml), chloramphenicol (4μg/ml), erythromycin (8μg/ml), rifampicin (0.5μg/ml) and gentamicin (1μg/ml) in clearing intracellular MRSA USA300 was determined in J774A.1 cells. Percent bacterial reduction was calculated in relative to the untreated groups. The results are given as means ± SD (n = 3). Combination therapy was compared to monotherapy and the P values of (**, ≤ 0.05) are considered as significant.
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pone.0133877.g006: Synergistic activities of EB with conventional antibiotics in vitro and in cell culture.(a) The Bliss Model for Synergy confirms the in vitro synergism with conventional antimicrobials (gentamicin, rifampicin, erythromycin, chloramphenicol, vancomycin, clindamycin and linezolid) against MRSA USA300. Degree of synergy was calculated in the presence of EB (0.0312 μg/ml) in combination with sub-inhibitory concentrations of conventional antimicrobials. (b) Synergistic activity of EB with conventional antimicrobials in infected cell culture. Efficacy of EB (0.5μg/ml) in combination with linezolid (4μg/ml), clindamycin (1μg/ml), vancomycin (4μg/ml), chloramphenicol (4μg/ml), erythromycin (8μg/ml), rifampicin (0.5μg/ml) and gentamicin (1μg/ml) in clearing intracellular MRSA USA300 was determined in J774A.1 cells. Percent bacterial reduction was calculated in relative to the untreated groups. The results are given as means ± SD (n = 3). Combination therapy was compared to monotherapy and the P values of (**, ≤ 0.05) are considered as significant.

Mentions: After confirming that EB has a potential use as an antibacterial agent for the treatment of infections caused by multidrug resistant pathogens, it was important to explore the synergistic relationship of EB with conventional antibiotics in vitro and in cell culture. With the rapid emergence of multidrug-resistant strains of S. aureus, monotherapy with single antibiotic has become less effective [46, 47]. Therefore, alternative strategies such as combinational therapy have been used in the healthcare setting to improve the morbidity associated with MRSA infections and to reduce the likelihood of emergence of resistant strains [1, 46, 48, 49]. To ascertain whether EB has the potential to be combined in vitro and in cell culture with conventional antimicrobials such as linezolid, clindamycin, vancomycin, chloramphenicol, erythromycin, rifampicin, and gentamicin against MRSA USA300, we used the in vitro Bliss independence model of synergism and infected cell culture assay [15]. In vitro results from the Bliss independence model of synergism are presented in Fig 6A. EB was found to exhibit a synergistic relationship with all tested conventional antimicrobials in vitro against MRSA USA300. Results of synergistic relationship of EB with conventional antimicrobials in infected cell culture against intracellular MRSA USA300 are presented in Fig 6B. Conventional antimicrobials (clindamycin, erythromycin, and rifampicin) showed synergistic activity when combined with EB and significantly reduced intracellular MRSA when compared to monotherapy. However, EB did not show synergistic activity with linezolid, vancomycin, chloramphenicol, or gentamicin in clearing intracellular MRSA. Identifying antibiotics that can be synergistically paired with EB can potentially prolong the clinical utility of these antibiotics and reduce the likelihood of emergence of resistant strains.


Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

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

Synergistic activities of EB with conventional antibiotics in vitro and in cell culture.(a) The Bliss Model for Synergy confirms the in vitro synergism with conventional antimicrobials (gentamicin, rifampicin, erythromycin, chloramphenicol, vancomycin, clindamycin and linezolid) against MRSA USA300. Degree of synergy was calculated in the presence of EB (0.0312 μg/ml) in combination with sub-inhibitory concentrations of conventional antimicrobials. (b) Synergistic activity of EB with conventional antimicrobials in infected cell culture. Efficacy of EB (0.5μg/ml) in combination with linezolid (4μg/ml), clindamycin (1μg/ml), vancomycin (4μg/ml), chloramphenicol (4μg/ml), erythromycin (8μg/ml), rifampicin (0.5μg/ml) and gentamicin (1μg/ml) in clearing intracellular MRSA USA300 was determined in J774A.1 cells. Percent bacterial reduction was calculated in relative to the untreated groups. The results are given as means ± SD (n = 3). Combination therapy was compared to monotherapy and the 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.g006: Synergistic activities of EB with conventional antibiotics in vitro and in cell culture.(a) The Bliss Model for Synergy confirms the in vitro synergism with conventional antimicrobials (gentamicin, rifampicin, erythromycin, chloramphenicol, vancomycin, clindamycin and linezolid) against MRSA USA300. Degree of synergy was calculated in the presence of EB (0.0312 μg/ml) in combination with sub-inhibitory concentrations of conventional antimicrobials. (b) Synergistic activity of EB with conventional antimicrobials in infected cell culture. Efficacy of EB (0.5μg/ml) in combination with linezolid (4μg/ml), clindamycin (1μg/ml), vancomycin (4μg/ml), chloramphenicol (4μg/ml), erythromycin (8μg/ml), rifampicin (0.5μg/ml) and gentamicin (1μg/ml) in clearing intracellular MRSA USA300 was determined in J774A.1 cells. Percent bacterial reduction was calculated in relative to the untreated groups. The results are given as means ± SD (n = 3). Combination therapy was compared to monotherapy and the P values of (**, ≤ 0.05) are considered as significant.
Mentions: After confirming that EB has a potential use as an antibacterial agent for the treatment of infections caused by multidrug resistant pathogens, it was important to explore the synergistic relationship of EB with conventional antibiotics in vitro and in cell culture. With the rapid emergence of multidrug-resistant strains of S. aureus, monotherapy with single antibiotic has become less effective [46, 47]. Therefore, alternative strategies such as combinational therapy have been used in the healthcare setting to improve the morbidity associated with MRSA infections and to reduce the likelihood of emergence of resistant strains [1, 46, 48, 49]. To ascertain whether EB has the potential to be combined in vitro and in cell culture with conventional antimicrobials such as linezolid, clindamycin, vancomycin, chloramphenicol, erythromycin, rifampicin, and gentamicin against MRSA USA300, we used the in vitro Bliss independence model of synergism and infected cell culture assay [15]. In vitro results from the Bliss independence model of synergism are presented in Fig 6A. EB was found to exhibit a synergistic relationship with all tested conventional antimicrobials in vitro against MRSA USA300. Results of synergistic relationship of EB with conventional antimicrobials in infected cell culture against intracellular MRSA USA300 are presented in Fig 6B. Conventional antimicrobials (clindamycin, erythromycin, and rifampicin) showed synergistic activity when combined with EB and significantly reduced intracellular MRSA when compared to monotherapy. However, EB did not show synergistic activity with linezolid, vancomycin, chloramphenicol, or gentamicin in clearing intracellular MRSA. Identifying antibiotics that can be synergistically paired with EB can potentially prolong the clinical utility of these antibiotics and reduce the likelihood of emergence of resistant strains.

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