Bacteria often attack with toxins² designed to hijack³ or even kill host cells. To avoid self-destruction, bacteria have ways of protecting themselves from their own toxins. Now, researchers at Washington University School of Medicine in St. Louis have described one of these protective mechanisms⁴, potentially paving the way for new classes of antibiotics⁶ that cause the bacteria's toxins to turn on themselves.

Scientists determined⁷ the structures of a toxin¹ and its antitoxin in Streptococcus pyogenes（酿脓链球菌） , common bacteria that cause infections ranging from strep throat to life-threatening conditions like rheumatic（风湿病的） fever. In Strep, the antitoxin is bound to the toxin in a way that keeps the toxin inactive.

"Strep has to express this antidote⁸, so to speak," says 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."

With that in mind, Smith and colleagues may have 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," says Thomas E. Ellenberger, DVM, PhD, the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular⁹ Biophysics at the School of Medicine. "A drug that would stabilize¹⁰ the inactive form of the immunity¹¹ factor would liberate¹² the toxin in the bacteria."

In this case, the toxin is known as Streptococcus pyogenes beta-NAD+ glycohydrolase, or SPN. Last year, coauthor Michael G. Caparon, PhD, professor of molecular microbiology, and his colleagues in the Center for Women's Infectious Disease Research showed that SPN's toxicity¹³ stems from its ability to use up all of a cell's stores of NAD+, an essential component¹⁴ in powering cell metabolism¹⁵（新陈代谢） . 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, researchers can now test possible drugs that might force the antitoxin to remain unbound to the toxin, thereby¹⁶ 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.

Understanding how these bacteria cause disease in humans is important in drug design.

"There is a war going on between bacteria and their hosts," Smith says. "Bacteria secrete¹⁷（藏匿） toxins and we have ways to counterattack（反击） through our immune systems and with the help of antibiotics. But, as bacteria develop antibiotic⁵ 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 today, there are no classes of drugs that take aim at the protective action of the bacteria's antitoxin molecules¹⁸.

"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."