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New Type of Antibiotic May Defeat Drug-Resistant Bugs

Researchers target growth-promoting thioredoxin system in bacterial cells (Dec. 18)

In an article published in the FASEB Journal, researchers at the Karolinska Institute in Sweden have described a new principle for fighting bacterial infections. The novel antibiotic mechanism is based on selectively blocking the thioredoxin system in cells, which is crucial to the growth of certain bacteria. The researchers hope to use the new approach to treat conditions such as stomach ulcers, tuberculosis (TB), and methicillin-resistant Staphylococcus aureus (MRSA).

“Much work remains to be done, but we believe that it will be possible to use this mechanism when, for example, broad-spectrum antibiotics have proved to be inadequate,” said study leader Professor Arne Holmgren.

The thioredoxin system is present in all cells and is central to the ability of cells to make new DNA. It is also important in protecting cells from oxidative stress, which arises when excess oxygen radicals and other oxidizing agents are formed. Oxidative stress may occur, for example, during attacks on bacteria by white blood cells, and it can damage or kill cells. The most important components of the thioredoxin system are the enzymes thioredoxin and thioredoxin reductase. Thioredoxin is required for the process of creating new DNA, and thioredoxin reductase ensures that the thioredoxin remains active.

In addition to the thioredoxin system, mammals (including humans) and some bacteria have a second, similar biochemical process in cells that is based on the enzyme glutaredoxin. The thioredoxin system and the glutaredoxin system act as each other’s backup. However, many bacteria that cause disease — such as Helicobacter pylori (which causes stomach ulcers), the TB bacterium Mycobacterium tuberculosis, and the multiresistant staphylococcus bacterium MRSA — have only the thioredoxin system. This makes them vulnerable to substances that inhibit thioredoxin and thioredoxin reductase.

“Furthermore, the thioredoxin reductases in bacteria are very different in chemical composition and structure from the human enzyme. And it is just these differences, and the fact that certain bacteria lack the glutaredoxin system, that mean that drugs that affect thioredoxin reductase can be used as antibiotics,” Holmgren said.

The researchers found that the drug candidate ebselen — which has been tested for the treatment of stroke and inflammation — and similar synthetic substances inhibit thioredoxin reductase in bacteria. In laboratory experiments, ebselen was able to kill certain types of bacteria but not others. Using Escherichia coli bacteria, the researchers “switched off” the genes in the DNA molecule that code for the glutaredoxin enzyme or the formation of the tripeptide glutathione, which is another important component of the glutaredoxin system. These genetically modified bacteria were found to be more susceptible to ebselen than normal.

Bacteria that are resistant to several different types of antibiotics are a serious and extensive problem all over the world, the authors point out. The method of attacking bacteria by preventing the construction of their cell walls, which was introduced when penicillin was discovered at the beginning of the 20th century, is still used today. Therefore, new ways of combating diseases caused by bacterial infections are long overdue, the authors say. They believe that the new antibiotic principle they have discovered may be part of the solution.

“It is particularly interesting that MRSA and antibiotic-resistant TB are also susceptible to ebselen and new synthetic substances,” Holmgren said. “And it’s worth noting that ebselen is an antioxidant, just as vitamin C is. This means that it protects the host against oxidative stress, and in this way we can kill two birds with one stone.”

Source: Karolinska Institute; December 18, 2012.

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