Dartmouth researchers have discovered the presence of a fatty acid that explains the function of Vibrio cholerae, the bacterium that causes cholera in humans, according to a study published Feb. 1 in an online edition of the Proceedings of the National Academy of Sciences. The findings could lead to the development of new drugs that prevent or treat the disease, according to chemistry professor Jon Kull, who co-authored the study.
"It's very rare that you have a basic scientific discovery that immediately suggests something that could be clinically significant," Kull said.
Cholera is a potentially fatal acute infection that causes diarrhea, which can result in severe dehydration and kidney failure. Diarrheal diseases kill 1.5 million children each year and are the second leading cause of death in children under five years of age globally, according to the World Health Organization web site.
V. cholerae, the bacterium that causes cholera, uses the protein ToxT to regulate toxin production and colonization, or the process by which the bacterium establishes itself in the human body, according to Dartmouth Medical School professor Ronald Taylor, another co-author of the study.
The bacterium also uses the ToxT protein to sense its location as it moves from the stomach to the intestines, Taylor said. Because stomach bile prevents the protein from functioning, the bacterium does not produce the toxins that cause severe diarrhea until it reaches the intestinal wall, he said.
Prior to the study, scientists did not understand on a molecular level why stomach bile prevented the bacterium from becoming harmful, Kull said.
"We've known for some time that bile and its components inhibit important virulence gene expression [of the bacterium]," Taylor said. "But we didn't have a direct connection."
The bacterium responds to changes in fatty acid concentrations in its surroundings to sense when it has reached the "right environment to infect," Kull said.
ToxT is inactive in the stomach where there is a high concentration of fatty acids due to stomach bile, but it becomes active in the lower concentrations of fatty acids in the intestinal wall, Kull said.
Using X-ray crystallography, Dartmouth researchers discovered a previously unknown unsaturated fatty acid in the structure of the ToxT protein that explains the reasons for the changes in the bacterium's behavior in the different environments, the researchers said.
The discovery of the fatty acid in the protein could lead to the development of drugs that would inhibit the function of the ToxT protein and prevent the bacterium from causing cholera, Taylor said.
Drugs that increase the concentration of fatty acids in the intestine or mimic the fatty acid's function in the ToxT protein could make current treatment of cholera "more efficient," Taylor said.
"We're hoping that we might be able to increase the concentration of fatty acids in these people," he said. "If the concentration is high enough [in the intestine], bacteria would not become virulent."
Unsaturated fatty acids are readily available as dietary supplements and are safe for human consumption, which means the Dartmouth researchers' findings could be applied toward medical treatments quickly and easily, according to Taylor.
The results of the study may be applicable to a larger spectrum of proteins that use a mechanism similar to the ToxT protein, according to chemistry professor Maria Pellegrini, a co-author of the study.
The bacteria that cause other diarrheal diseases such as dysentery and typhoid fever may have regulatory proteins that have similar structures to that of ToxT, Kull said. If the virulence of these bacteria is also regulated by fatty acids, researchers may be able to greatly reduce the global impact of diarrheal diseases.
The researchers are "very cautiously optimistic" that drugs for cholera treatment through the regulation of fatty acids may be effective in treating other diarrheal diseases as well, Kull said.
Other authors of the study were Michael Lowden, a member of the technical staff in the chemistry department, summer undergraduate research fellow Michael Chiorazzo and DMS professor Karen Skorupski.