Ebselen Readily Kills Bacteria Lacking the Glutaredoxin Antioxidant System

A drug being investigated as a possible treatment for reperfusion injury, stroke, and tinnitus has been found to selectively kill bacteria that lack the glutaredoxin system.

Some types of bacteria lack the gluaredoxin system, which functions similarly to the thioredoxin system in cellular DNA synthesis and as a defense against oxidative stress, and are, therefore, completely dependent on thioredoxin reductase (TrxR) and thioredoxin (Trx) for survival. Of particular interest to drug developers is the fact that TrxR is very different in structure and mechanism in mammals and bacteria.

Investigators at the Karolinska Institutet (Stockholm, Sweden) worked with the drug ebselen (2-phenyl-1, 2-benzisoselenazol-3(2H)-one), a well-known antioxidant and a substrate for mammalian TrxR and Trx. Their study was based on earlier findings that ebselen was rapidly bacteriocidal for methicillin-resistant Staphylococcus aureus by an unknown mechanism.

The investigators reported in the December 17, 2012, online edition of the FASEB Journal that ebselen was a competitive inhibitor of Escherichia coli TrxR through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx were essential for DNA synthesis, were particularly sensitive to ebselen. In growth-inhibited E coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH-negative pathogens, and ebsulfur inhibited a clinically isolated culture of Helicobacter pylori, the organism responsible for gastric ulcers and with a possible link to stomach cancer.

"This new antibacterial principle provides better chances of surviving an infection," said senior author Dr. Arne Holmgren, professor of biochemistry at the Karolinska Institutet. "Since ebselen is also an antioxidant, the present mechanism can be described as a "two for the price of one" antioxidant action in inflammation, and specific targeting of multiresistant bacterial complications and sepsis."

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