Making the less obvious choice can sometimes pay off. It certainly worked for a team of researchers hunting for an antibacterial agent that would act specifically against Helicobacter pylori, the bacterium that causes stomach ulcers. Stewart Fisher at AstraZeneca in Waltham, Massachusetts, and his colleagues picked an unlikely target, the enzyme glutamate racemase. “We chose a broad-spectrum target,” says Fisher. “Many people thought we would get broad-spectrum compounds. But we found the opposite to be true.”

The current therapy for H. pylori infection is a cocktail of two antibacterials and an antacid. Because each antibiotic acts broadly, wiping out both good and bad bacteria in the gut, the treatment has many side effects. And patients find that taking three different medicines each day makes it harder to comply with the regimen. So the AstraZeneca team wanted to find a single, selective treatment for H. pylori.

Glutamate racemase converts L-glutamate, one of the main sources of energy for H. pylori, to D-glutamate, which is then used as building material for the bacterial cell wall. “We chose the cell-wall synthesis pathway because it has already been proved to be an effective target with many different antibacterial agents,” says Fisher. “We chose this particular enzyme because it has never been targeted.”

Many species of bacteria contain glutamate racemase. But preliminary biochemical tests and sequence analysis had suggested to Fisher and his colleagues that the versions were sufficiently different to identify selective compounds against the H. pylori enzyme. Making use of resources and expertise at the company's labs in Massachusetts and Mölndal, Sweden, the team carried out an exhaustive series of biochemical and structural studies. “The more we learned, the more convinced we became that the proteins in different species had distinct properties,” says Fisher.

Ultimately, these studies, which ran from 1998 to 2005, identified at least three distinguishable forms of the enzyme (see page 817), each with a unique regulatory mechanism. “The molecules all seem to have come from the same basic monomer, but each bacterial species evolved in a different way to regulate the enzyme according to its needs,” says Fisher. The team then exploited the distinguishing features among the enzymes to identify selective inhibitors for the enzyme belonging to H. pylori. “The compounds we identified were highly selective,” says Fisher.

Although successful, the project did not always run smoothly. When the researchers first identified inhibitors against the H. pylori enzyme, for instance, they couldn't fathom how they might be working, because they bore no structural similarity to the substrate, glutamate. Using a combination of techniques, Fisher and his colleagues discovered that the inhibitors were acting through an additional, previously unknown binding site.

And the researchers' perseverance may have paid off in more ways than one. During the course of the study, evidence emerged that H. pylori is linked to stomach cancer. Narrow-spectrum agents against H. pylori could therefore serve not only to replace current therapies, but also as prophylactics against ulcers and cancer.