Small molecule inhibitor of cholera discovered

October 14, 2005

Just as hurricanes in the Gulf states and Guatemala have raised the risks of cholera outbreaks, researchers at Harvard Medical School have identified a new type of antibiotic against the cholera bacteria. While traditional antibiotics kill bacteria outright by interfering with processes essential for their survival, the new agent blocks production of bacterial proteins that cause the severe diarrhea associated with Vibrio cholerae infection.

"What we have done is made a custom, organism-specific antibiotic against Vibrio cholerae," said John Mekalanos, the Adele Lehman professor of microbiology and molecular genetics at HMS and the senior author on a report of the work appearing in today's online edition of Science.

Using a high-throughput screen of 50,000 small molecule candidate compounds, Mekalanos and lead author Deborah Hung identified several that turned off the expression of virulence proteins, factors that help the bacteria invade its human host and cause disease. They then showed that the most promising compound prevented cholera bacteria from setting up an infection when introduced into the digestive tract of mice.

Since most disease-causing organisms use elaborate virulence factors such as toxins to do their damage, the new approach should be widely applicable. "There is no reason our results cannot be replicated for a number of other important pathogens," Mekalanos said.
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Harvard Medical School

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