A group of researchers from Dartmouth College have solved the structure of ToxT, a protein regulator of the infectious bacterium Vibrio cholerae that is essential to cause the potentially fatal diarrheal disease of cholera. Their study may lead to a novel method to inhibit infection of a disease afflicting nearly 300,000 people per year worldwide.
The high resolution structure of ToxT that the researchers uncovered using x-ray crystallography shares features common to other protein regulators, but also contains a buried component that “caught researchers by surprise: a single hidden 16-carbon fatty acid,” says John Kull, one of the chief investigators of the study and associate professor of chemistry at Dartmouth College.
The newly-found fatty acid turned out to inhibit expression of key virulence factors vital for cholera infection to produce disease for as long as the fatty acid remained attached to the ToxT regulator. The fatty acid is thought to be released and the bacterium able to colonize only when ToxT reaches the mucus lining of the small intestine, an area that is low in bile-a fluid in the intestine already known to inhibit expression of these virulence factors of Vibrio cholerae.
The researchers found that the presence of oleic acids, found abundantly within the human gut but present in much lower concentrations in the mucus lining of the small intestine, is what prevents ToxT from releasing this inhibitory fatty acid.
Consequently, the research team has been led to hypothesize that providing individuals infected by the Vibrio cholerae bacterium with an increased supply of oleic acids or other similar compounds, preferably from a natural source, may serve as a possible mechanism to control the bacterium’s virulence.
Oleic acid naturally binds to the ToxT regulator, says Kull. “If you can get enough of it in your system, it might be able to prevent cholera infection from resulting in disease.”
Despite the existence of a cholera vaccine Kull, says, “A natural product would be much cheaper.” Because unclean water sources are a major cause of cholera outbreaks, cholera afflicts greater numbers in third world countries-making drug cost a primary issue for defeating the illness worldwide.
Another advantage of prescribing a natural product rich in oleic acid to individuals infected by the cholera bacterium is that it would not kill it, so there’s no selective pressure to enable the bacteria to gain resistance toward the ‘drug.’ Classes of drugs that disable rather than kill bacteria are becoming increasingly popular for manufacturers due to increasing bacterial resistance to antibiotics.
If 300,000 cholera infections worldwide per year is not a large enough number to spark interest as well as increase funding for this study, it is known that 44 billion people worldwide fall ill with infectious diarrhea each year, resulting in six to eight million subsequent deaths.
“If these bacteria are all regulated in the same way and this natural treatment works for cholera,” says Kull, “It could work for all of these diseases as well. And that is a too big to believe deal.”
The publication can be found at
http://www.pnas.org/content/early/2010/01/27/0915021107.full.pdf+html
A poorly written article. It has too many grammatical mistakes and it does not adequately address the issue at hand.