Discovery of bugs’ self-protective mechanism raises hope

Now,researchers at the Washington University School of Medicine in St Louis determined the structures of a toxin and its antitoxin in Streptococcus pyogenes — a common bug that cause infections ranging from strep throat to life-threatening conditions like rheumatic fever.

In strep,the researchers found that the antitoxin is bound to the toxin in a way that keeps the toxin inactive. “Strep has to express this antidote,so to speak. If there were no antitoxin,the bacteria would kill itself,” said Craig Smith,a postdoctoral researcher and first author of the study appeared in the journal Structure.

With that in mind,Smith and his colleagues found a way to make the antitoxin inactive. They discovered that when the antitoxin is not bound,it changes shape. “That’s the Achilles’ heel that we would like to exploit,” Thomas Ellenberger,co-author of the study,said,adding the finding would lead to new class of drugs to contain bacteria infections.

“A drug that would stabilize the inactive form of the immunity factor would liberate the toxin in the bacteria,” he said.

In this case,the toxin is known as SPN and past studies have already shown that its toxicity stems from its ability to use up all of a cell’s stores of an essential component in powering cell metabolism,called NAD+.

The antitoxin,known as the immunity factor for SPN,or IFS,works by blocking SPN’s access to NAD+,protecting the bacteria’s energy supply system.

With the structures determined,the researchers said they can now test possible drugs that might force the antitoxin to remain unbound to the toxin,thereby leaving the toxin free to attack its own bacteria. “The most important aspect of the structure is that it tells us a lot about how the antitoxin blocks the toxin activity and spares the bacterium,” said Ellenberger.

Understanding how these bacteria cause disease in humans is important in drug design,the researchers said.

Smith said,”There is a war going on between bacteria and their hosts. Bacteria secrete toxins and we have ways to counterattack through our immune systems and with the help of antibiotics.

“But,as bacteria develop antibiotic resistance,we need to develop new generations of antibiotics.”

Many types of bacteria have evolved this toxin-antitoxin method of attacking host cells while protecting themselves. But there are no drugs that take aim at the protective action of the bacteria’s antitoxin molecules.