Medical researchers turning bacteria against themselves

Posted by David Gomez

Bacteria usually attack you with toxins designed to hijack or even kill host cells. To avoid self-destruction, bacteria possess a way of protecting themselves from their own toxins.

Medical scientists at Washington University School of Medicine in St. Louis have described one of these protective tools, leading the way for the development of new classes of antibiotics that cause the bacteria’s toxins to turn on themselves.
    
According to a press release researchers determined the configuration of a toxin and its antitoxin in Streptococcus pyogenes, common bacteria that are the cause of infections ranging from strep throat to deadly ailments like rheumatic fever.

In Strep, the antitoxin is connected to the toxin in a way that allows it to keep the toxin inactive.
    
"Strep has to express this antidote, so to speak," said Craig L. Smith, PhD, a postdoctoral researcher and first author on the paper that appears Feb. 9 in the journal Structure. "If there were no antitoxin, the bacteria would kill itself."
    
Now that they know that, Smith and colleagues may have found a way to make the antitoxin inactive. They learned that when the antitoxin is not bound, it changes shape.
    
"That’s the Achilles’ heel that we would like to exploit," says Thomas E. Ellenberger, DVM, PhD, the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics at the School of Medicine. "A drug that would stabilize the inactive form of the immunity factor would liberate the toxin in the bacteria."
    
In this situation, the toxin is known as Streptococcus pyogenes beta-NAD+ glycohydrolase, or as the much shorter and easier to say name: SPN.

Last year, coauthor Michael G. Caparon, PhD, professor of molecular microbiology, and his associates in the Center for Women’s Infectious Disease Research proved that SPN’s toxicity stems from its ability to use up all of a cell’s reserves of NAD+, a key component in powering cell metabolism.

The antitoxin, known as the immunity ingredient for SPN, or IFS, functions by blocking SPN’s access to NAD+, preserving the bacteria’s energy supply system.
    
Because the structures determined, researchers can now begin testing possible drugs that might press the antitoxin to remain unbound to the toxin, basically 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," says Ellenberger.
    
Having usable knowledge of how these bacteria cause sickness in humans is crucial in drug design.
    
"There is a war going on between bacteria and their hosts," Smith says. "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."
    
Various kinds of bacteria have refined this toxin-antitoxin manner of attacking cells while protecting themselves. Currently, there are no types of drugs that target the protective nature of the bacteria’s antitoxin molecules.
    
"Obviously they could evolve resistance once you target the antitoxin," Ellenberger says. “But this would be a new target. Understanding structures is a keystone of drug design."