Duke researchers have discovered a new way to inhibit the infectious bacteria Francisella tularensis, infamous for its potential as a bioweapon.
The team of biochemists uncovered that Francisella tularensis becomes virulent through its unusual interactions with proteins. Left unchecked, the bacterium can cause the disease tularemia, which can prove fatal if not immediately treated.
“If some group finds a way to make [Francisella tularensis] resistant to antibiotics and uses it as a bioweapon, the result would be scary,” said Professor of Biochemistry Maria Schumacher, who was involved with the study.
Francisella tularensis is listed as a bioterrorism agent by the Centers for Disease Control, she added. A person only has to inhale 10 microscopic particles of the bacterium to become infected.
Richard Brennan, James B. Duke professor of biochemistry and chair of the biochemistry department, explained that although the human immune system is capable of killing the bacteria, it often isn't able to effectively do so.
If the bacteria invades particularly vulnerable parts of the body, the damage inflicted could be deadly, he said.
Schumacher explained that it takes a series of reactions for the bacteria to be virulent after it infects a host. Researchers had previously been unaware of how this process was regulated for Francisella tularensis until now.
“We have found that there’s a ‘switch’ that turns on the entire process,” Schumacher said. “That’s the key [to stop the virulence].”
The team found that after invading a cell, Francisella tularensis interacts with a molecule called ppGpp. ppGpp then binds to a special protein complex, which triggers the bacteria to replicate and spread into other cells.
Schumacher said that their findings could help guide researchers in developing drugs that target ppGpp or its binding to the protein complex—stopping the disease in its tracks.
“[Our study shows] you don’t even need to kill the bacterium to cure the disease,” Brennan said. “You only need to block the formation of the complex.”
Antibiotics are the most common and effective treatment of tularemia at present, Schumacher noted.
To establish the bacteria's activities within the cell, the researchers used x-ray crystallography to identify how proteins react to the infection, said Bonnie Cuthbert, a Ph.D. student in biochemistry and first author of the study.
“What crystallography provides is like a 3-D snapshot of what is actually happening in the protein,” she said.
Schumacher explained that although crystallography techniques can eventually provide a wealth of data, it is challenging to first create crystal structures that accurately represent the characteristics of each protein.
“Proteins are like people—every protein is different,” she said. “You have to know your protein [to reproduce it in a crystal structure].”
Finding a protein's unique structure can aid researchers in carrying out more complicated experiments as well as designing novel therapies, Brennan added.
Identifying ppGpp's role in the replication process was accomplished with the help of collaborators at at Harvard Medical School and University of Wisconsin-Madison.
Cuthbert explained that researchers at the Harvard Medical School first identified ppGpp as a candidate molecule involved in making Francisella tularens virulent, but used Duke's help in unravelling the specifics of its role.
The verification process at Duke required several biochemical experiments including crystallography, she said. Another group of ppGpp researchers at University of Wisconsin-Madison then used some of their own techniques to verify the mechanism Duke's crystal structures had suggested for ppGpp binding.
“As a scientist, I’m really excited when we all independently come to the same result,” Cuthbert said. “It strengthens our original conclusion.”
Cuthbert said that she first became interested in Francisella tularensis when she earned that other bacteria do not cause native interactions between proteins like the one ppGpp does to the protein complex.
“What is amazing about science is it’s full of the unexpected,” she said.