A drug currently being used to treat ischemic strokes may prove to be a significant advance in the treatment of tuberculosis and ulcers. In a new research report appearing online in The FASEB Journal, a compound called ebselen effectively inhibits the thioredoxin reductase system in a wide variety of bacteria, including Helicobacter pylori which causes gastric ulcers and Mycobacterium tuberculosis which causes tuberculosis. Thioredoxin and thioredoxin reductase proteins are essential for bacteria to make new DNA, and protect them against oxidative stress caused by the immune system. Targeting this system with ebselen, and others compounds like it, represents a new approach toward eradicating these bacteria.
“This new antibacterial principle provides better chances of surviving an infection,” said Arne Holmgren, M.D., Ph.D., a researcher involved in the work from the Division of Biochemistry in the Department of Medical Biochemistry and Biophysics, at Karolinska Institutet in Stockholm, Sweden. “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 multi-resistant bacterial complications and sepsis.”
Building on previous observations where ebselen has shown antibacterial properties against some bacteria, Holmgren and colleagues hypothesized that the bacteria sensitive to ebselen relied solely on thioredoxin and thioredoxin reductase for essential cellular processes. They investigated this by testing it on strains of E. coli with deletions in the genes for thioredoxin, thioredoxin reductase and the glutaredoxin system. They found that strains with deletions in the genes coding for glutaredoxin system were much more sensitive than normal bacteria. Researchers further tested ebselen against Helicobacter pylori and Mycobacterium tuberculosis, which both naturally lack the glutaredoxin system and are frequently resistant to many commonly used antibiotics, and found both to be sensitive to ebselen.
“As rapidly as these organisms evolve, we need new drugs sooner rather than later,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “The fact that these scientists have found a new target for killing some of the most resistant bacteria is great news, but the fact that we already have at least one drug which we could possibly use now makes the news even better.”
Details: Research Communication: Jun Lu, Alexios Vlamis-Gardikas, Karuppasamy Kandasamy, Rong Zhao, Tomas N. Gustafsson, Lars Engstrand, Sven Hoffner, Lars Engman, and Arne Holmgren. Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione. FASEB J doi:10.1096/fj.12-223305