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Dam the bacteria, drugs and vaccines ahead.

Growing in a test tube, bacteria may appear harmless. When they infect a host, however, the microbes draw upon a concealed repertoire of molecular tools to dodge immune defenses and cause disease. Much like the famed Trojan horse, bacteria "hide their weapons until they're inside," notes Michael J. Mahan of the University of California, Santa Barbara.

In the May 7 SCIENCE, Mahan and his colleagues show that a protein called DNA adenine methylase, or Dam, regulates a bacterium's use of its armament. Without Dam, it's no longer virulent.

The findings suggest that Dam offers an appealing target for new antibiotics. Moreover, bacteria weakened by mutations in the gene for Dam might serve as vaccines against many diseases.

Like other methylases, Dam chemically coats DNA with clusters of atoms known as methyl groups. In doing so, it governs bacterial processes such as DNA replication and repair.

Mahan's group established the protein's role in virulence by disabling its gene in Salmonella typhimurium, which causes food poisoning in people and typhoid fever in mice. When researchers infected rodents with bacteria unable to make Dam, disease rarely resulted.

Mahan's team had previously identified around 250 genes activated in S. typhimurium when it infects a host. In the mutant bacteria, as many as 50 of these genes become active when the microbes are grown outside a host in test tubes. Dam seems to normally repress the genes until needed during an infection.

Unleashing the genes at the wrong time during an infection can prove troublesome to a bacterium. Furthermore, the mutant bacteria may overproduce some surface proteins, making them easier for the immune system to spot.

The investigators suggest that drugs that disable Dam will prove helpful in the fight against bacteria that have evolved resistance to traditional antibiotics.

"It's a nice target. It's a protein unique to bacteria, and its effect on virulence is spectacular," agrees Josep Casadesus of the University of Seville in Spain, who recently did experiments with results very similar to Mahan's group's.

While almost all bacteria employ Dam, investigators must still prove that the protein regulates virulence in more than this one species. The pervasiveness of Dam among bacteria raises a concern about any drug that targets the protein. "You could affect all the good bacteria in the gut," says Casadesus.

Disabling Dam weakens but doesn't actually kill bacteria. Salmonella bacteria without the methylase infect gut cells but don't advance deeper within a mouse, where they normally cause disease. Infections with the mutant bacteria protected mice from subsequent doses of unaltered salmonella.

"They stimulate the hell out of the immune system, but they don't proceed. It's the perfect vaccine," says Mahan, who has launched a company based on the new research. Its first goal is a vaccine that immunizes chickens from the salmonella that causes food poisoning. Dam-based vaccines may also thwart bacteria that cause cholera, the plague, and typhoid fever, Mahan says.
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Title Annotation:protein DAM, or DNA adenine methylase, that regulates how bacteria cause disease and why it should be a target for new antibotics that can diffuse the bacteria's virulence
Author:Travis, J.
Publication:Science News
Date:May 8, 1999
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