Ulcer bacterium's drug resistance unmasked.

By any measure, the drug metronidazole is a potent disease fighter. Also known as Flagyl, MetroGel, and Protostat, it knocks out the bacterium Helicobacter pylori, as well as microbes that can cause amoebic dysentery, other intestinal ailments, and some vaginal infections.

In 1985, scientists fingered the spiral-shaped H. pylori as the agent responsible for stomach ulcers and have since relied chiefly on metronidazole in combination with other drugs to battle the illness. H. pylori has proved to be a worthy adversary, however, developing widespread resistance to metronidazole.

Canadian and U.S. researchers have now discovered how some H. pylori infections succumb to metronidazole and others withstand its onslaught.

In a search through H. pylori genes taken from individuals in Peru and Lithuania, where the bacterium is common, the scientists identified genetic sequences that make the microbe drug-resistant and differentiated them from normal sequences.

One of the enzymes made by normal H. pylori converts metronidazole into a harsh chemical called hydroxylamine--a protein-busting, DNA-damaging terror that causes mutations in H. pylori's own genes. The besieged bacterium fights furiously to stem this DNA destruction. "If the rate of DNA damage is higher than the rate of repair, the cell dies," says microbiologist Avery C. Goodwin of Dalhousie University in Halifax, Nova Scotia.

Bacteria that escape the chemical reaper often have genetic mutations. If the gene encoding the enzyme that acts on metronidazole is damaged or destroyed, the bacterium becomes resistant to the drug. He and his colleagues report the findings in the April 14 Molecular Microbiology.

"This goes a long way toward helping us to understand metronidazole resistance in H. pylori," says Martin J. Blaser, a microbiologist at Vanderbilt University in Nashville. Having identified the enzyme's critical role, researchers may eventually develop a compound that restores susceptibility, he says. In addition, the discovery of this novel resistance pathway, which is based on a disabled or missing enzyme, may provide insights into H. pylori's unusual metabolic structure, which is neither entirely aerobic--oxygen-using--nor anaerobic.

Roughly one-third of people in the United States and Western Europe harbor H. pylori, and the proportion is higher in Asia and developing countries. Resistance to metronidazole among infected people is estimated at 40 percent in Europe and more than 70 percent in the developing world.

Although no biological connection has been demonstrated, epidemiological studies have linked H. pylori and stomach cancer. The bacterium may act by weakening the stomach lining's defenses against gastric acid, says study coauthor Douglas E. Berg, a microbial geneticist at Washington University in St. Louis. This can lead to chronic inflammation and a precancerous condition. Other research suggests that H. pylori may also disrupt programmed cell death, a natural check on runaway cell growth.

The researchers speculate that hydroxylamine, which can cause mutations in human as well as bacterial DNA, could contribute to the eventual development of gastric cancer. Delivering such a carcinogen to the cells of the stomach lining, Berg says, "strikes me as a very sobering and slightly scary type of thing."

Although this research is "fascinating," says Miklos Muller, a biochemical parasitologist at Rockefeller University in New York, the cancer connection to metronidazole is unlikely because hydroxylamine is short-lived in the stomach. Researchers looking for increased cancer risks linked to metronidazole haven't found convincing evidence, he says.