Closing the door on a global health threat
Thanks to modern water treatment and sewage systems, U.S. residents haven’t had to worry about cholera outbreaks since the early 1900s. But the disease, caused by infection with a bacterium that contaminates food and water in areas where sanitation is poor, is a serious health problem in almost every developing country. Since 2005, cases of cholera have been on the rise worldwide, and some studies suggest that severe weather events triggered by global warming may further the spread of this and other water-borne infectious diseases.
Although cholera—an intestinal infection that causes severe diarrhea and vomiting—can lead to dehydration and death if patients aren’t treated promptly with rehydration therapy, the illness does respond to antibiotics. These drugs, usually reserved for severe cases, can shorten the course and reduce the severity of the disease, but concerns about antibiotic resistance are spurring scientists like Maria Sandkvist to look for alternatives.
Rather than killing the cholera bug Vibrio cholerae, Sandkvist wants to interfere with its ability to make people sick, which it accomplishes by secreting a potent poison known as cholera toxin.
“If we can understand exactly how the toxin is secreted, we may be able to block its exit,” says Sandkvist.
Her research group is focusing on a particular apparatus in bacterial cells known as T2SS, which provides a pathway for the secretion of cholera toxin and other molecules. They’ve learned that T2SS is made up of at least 15 proteins, and now they’re studying those proteins in detail, trying to figure out how they fit together and interact with one another.
“It’s puzzle work,” says Sandkvist. But unlike the process of assembling a jigsaw puzzle while referring to the complete picture on the box top, “we’re working without a cheat sheet.”
The researchers know that T2SS spans the inner and outer membranes that surround the sausage-shaped bacterium and that the apparatus forms a channel through which the toxin is secreted. By studying T2SS’s structure in detail, Sandkvist hopes to find clues that will help chemists design drugs to plug the channel and block the toxin’s egress.
In a related endeavor, Sandkvist is searching for ready-made exit blockers. She’s working with scientists at U-M’s Center for Chemical Genomics, where a library of more than 50,000 chemical compounds—some known drugs and others likely candidates—along with automated sample-handling equipment, make it possible to rapidly screen large numbers of compounds for their ability to prevent secretion. Once promising prospects have been identified, Sandkvist and coworkers will be looking to see what these channel blockers have in common and which among them are most effective, in hopes of zeroing in on key features that characterize the most proficient plugs.
Although Vibrio cholerae and cholera toxin are Sandkvist’s primary interests, anything she learns about T2SS may have broader applications.
“We know that cholera toxin is secreted through the system we’re studying, but other proteins are transported simultaneously,” Sandkvist says. “We’re trying to determine if they’re also involved in causing disease.” What’s more, a rogue’s gallery of other disease-causing bacteria uses the same pathway for secreting their own toxins. One example is the notorious “hamburger pathogen” Escherichia coli O157:H7, which infects people who eat contaminated, undercooked ground beef (or other contaminated foods), causing bloody diarrhea and occasionally kidney failure and death.
“Once we understand how to block the passage of cholera toxin,” says Sandkvist, “we may be able to block the process in other pathogens and discover ways to prevent a number of other infectious diseases.”
