Bacteria Say NO To Drugs

Many species of bacteria express enzymes that synthesize nitric oxide (NO) from arginine, but so far the physiological role of such bacterial NO synthases has been a mystery. Now, Evgeny Nudler and colleagues at New York University School of Medicine have shown that endogenously produced NO protects bacteria from a broad spectrum of natural and synthetic antibiotics (Science 2009, 325, 1380). Their results suggest that inhibiting NO synthase in disease-causing bacteria could enhance the efficacy of antimicrobial therapy.

To determine the function of bacterial NO synthase, the researchers deleted the gene encoding the enzyme in three species of bacteria. The strains lacking NO synthase grew similarly as the wild-type bacteria under normal conditions, but were more sensitive to many antibiotics of diverse cellular targets and structures, such as lactams, aminoglycosides, and quinolones.

Nudler and coworkers show that NO increases 
the antibiotic resistance of several species of bacteria, including harmful human pathogens, by two mechanisms. First, NO⁺, a product of NO oxidation, directly modifies some antibiotics. Second, NO protects 
bacteria against oxidative stress. In addition to inhibiting specific cellular targets, many antibiotics kill bacteria by promoting the formation of cell-damaging reactive oxygen species such as hydroxyl radicals and superoxide anions. NO not only inhibits chemical reactions that produce these reactive oxygen species, but also activates two enzymes that reduce oxidative stress.

The study helps explain how bacteria can coexist with microorganisms that produce natural antibiotics, says Carl Nathan, a professor of microbiology at Weill Cornell Medical College. But he notes that for therapeutic applications, NO synthase inhibitors should specifically target the bacterial enzyme while sparing mammalian NO synthases, which play important physiological roles. “It might be difficult to identify one compound that targets multiple bacterial species’ NO synthases but none of the host’s NO synthases,” he says.