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NO Good: Nitric Oxide May Be Key to Overcoming Antibiotic Resistance

Recent discoveries have shown how some bacteria use a form of nitric oxide to launch more effective attacks on their hosts. Can the new knowledge be translated into better drugs to beat antibiotic-resistant MRSA or anthrax?
no fighiting antibiotic resistance



ISTOCKPHOTO/CWLAWRENCE

Researchers may be a touch closer to eliminating antibiotic-resistant bacteria, such as MRSA (methicillin-resistant Staphylococcus aureus) and anthrax, thanks to a troublesome air pollutant—nitric oxide (NO).

In the body, however, the compound plays a range of crucial roles—assisting with processes ranging from brain function to penile erection. Recent studies have discovered that NO also helps bacteria protect themselves. "This particular function of NO [is] important in making pathogens virulent," says Evgeny Nudler, a professor of biochemistry at New York University Langone Medical Center in Manhattan.

A new study, co-authored by Nudler and published online yesterday in Science, shows that stopping the creation of bacterial nitric oxide synthases (NOS), enzymes that contribute to the production of NO, may leave the microbes more vulnerable to antibiotic treatment.

Many antibiotics help kill off their targets by subjecting them to severe oxidative stress, but NO works to protect bacteria from this sort of attack. "That contribution actually appears to be significant and underappreciated," Nudler says.

The findings have clear implications: If researchers could adapt NOS inhibitors, which are already commercially available, to be safe and effective in antibiotic treatments, even the toughest MRSA or Bacillus anthracis strains (which cause anthrax) might not be able to stand up to a drug's oxidative stress load.

The key to the effectiveness of NOS inhibitors is that resistant bacterial strains are not completely impervious to the drugs. They can, however, survive antibiotics at higher dosages than are safe to administer in humans. Being able to lower the bacteria's ability to fend off a medication's oxidative stress would enable smaller doses of antibiotics to be effective. And "anything that would allow us to decrease the working concentration would be great," Nudler says.

Nudler and his team are already working on animals to study the safety and effectiveness of putting their findings to work. He hopes to have provisional data in by year-end.

Given that NO plays an important role in regulating bodily functions, such as blood pressure and coagulation, an inhibitor treatment might bring along some evident side effects. But, Nudler says, existing treatments could dampen many of the potential side effects and, in any case, might well be worth a victory over an acute infection.

Bacteria wielding NOS are not limited to virulent human infections. In fact, the enzyme has also been noted in soil bacteria. Some plant pathogens, such as those responsible for costly potato diseases, can also generate NOS. In plants, it works both to defend the bacteria and to break down part of the plant's natural defenses. "It's certainly a logical way to improve virulence," says Rosemary Loria, a professor in Cornell University's Department of Plant Pathology and Plant–Microbe Biology in Ithaca, N.Y., whose lab produced a 2008 paper describing the phenomenon in the journal Chemistry & Biology. On the agricultural front, Loria and her team also hope to be able to make use of the findings in making plants more resistant to such attacks.

Big questions remain as to exactly how and why these bacteria create NOS—and why more do not do it. "The exact mechanisms are not clear," Nudler says. The compound also appears to serve other bacterial functions, such as signaling, which could provide more clues about how to halt it. But getting to the bottom of exactly how the nitric oxide synthases defense mechanism works will likely help researchers better tune treatment in the future.

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