New Antibiotic Could Fight Cholera

Gene-targeted virstatin might also battle other lethal infections

THURSDAY, Oct. 13, 2005 (HealthDay News) -- A new strategy for antibiotic development has produced a drug that's effective against cholera in animal tests and could produce a host of bacteria-fighting compounds against other diseases, researchers report.

"Existing antibiotics can target bacteria as they grow in test tubes," said Dr. Deborah T. Hung, an instructor in medicine at Harvard Medical School and lead author of a report published in the Oct. 13 online issue of Science.

"This new class we are proposing doesn't have any significant effect on bacteria in a test tube. Only during infection does it become effective," Hung said.

A molecule that the Harvard researchers have named "virstatin" targets two critical genes of the cholera bacterium -- one that enables it to take up residence in the intestine and another that produces the toxin responsible for diarrhea and other debilitating symptoms of infection.

The hope is that virstatin, or an improved version of it, can someday be used with conventional antibiotics to treat cholera, Hung said. An effort to find such a compound has begun in the Harvard laboratory of John J. Mekalanos, chairman of microbiology and molecular genetics.

Virstatin's discovery was built on a quarter-century of research on the cholera bacterium, Mekalanos explained. "We identified many individual genes, learned how the toxin was assembled and how it was exported," he said. "Given all that, we were confident that there were many different steps in the process where a small molecule could interfere with it."

Their research relied on a vast library of chemicals the laboratory had assembled over the years. A first search of the library turned up 100 likely candidates, Mekalanos said. "Then we narrowed it to a dozen that looked promising, hitting the pathway in the last step, the last regulatory protein needed to express the toxin."

Nature then gave the researchers an unexpected bonus: it turned out that the same molecule that stopped production of the toxin also interfered with the ability of the bacteria to colonize the intestine.

Tests with mice showed that the drug not only helped prevent infection, but also improved recovery after infection.

"This is the first evidence that one can use chemical compounds of this sort to control virulence inside an animal model," Mekalanos said. "This opens the possibility of designer drugs for every pathogen."

A number of laboratories across the country are experimenting with the same approach, he said. The work has been given impetus because of the possibility of terrorist attacks using bacteria such as anthrax and plague, Mekalanos said.

One major advantage of the new approach is that it can fight the tendency for bacteria to become resistant to conventional antibiotics, he said. Because virstatin would be given only to people with cholera, "we don't have to worry about other antibiotics becoming resistant in other diseases," Mekalanos said.

The ongoing testing of chemical analogs to virstatin is aimed at producing a more powerful version of the molecule, Hung said. That would mean that the dose given could be smaller. The researchers hope for at least a 10-fold and perhaps a 100-fold improvement in effectiveness over that already shown in mice.

Cholera, often spread by contaminated water, is rare in the United States but kills tens of thousands of people in developing countries.

Human trials have not yet been planned, Hung said. "Cholera is an easy disease to do trials on," she said. "But it's a little premature."

The finding is important for several reasons, said Steven R. Blake, an associate professor of microbiology at the University of Illinois at Urbana.

"Increasing resistance to antibiotics underscores the need for new strategies for fighting infection," he said. "This establishes a paradigm for a new class of drugs. The idea of virstatin as an inhibitor of virulence is really a new pathway in anti-infective activity, different from conventional approaches."

The specificity of virstatin eliminates one major disadvantage of current antibiotics -- the possibility that they might attack normal, unharmful bacteria as well as disease-causing bacteria, he said.

And finally, "this validates the approach of screening large libraries of chemicals randomly," Blake said.

More information

Learn more about cholera from the U.S. Centers For Disease Control and Prevention.

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