Research has found a promising starting point for the creation of drugs that can cure Clostridium difficile (C. diff), a potentially fatal virulent health care-associated infection that causes severe diarrhea, nausea, and internal bleeding. Through investigating a type of toxin released by the most dangerous strains of C. diff, researchers now have a map for developing drugs that can block the toxin and prevent the bacteria from entering human cells.
A combination of cryogenic electron microscopy, X-ray crystallography, nuclear magnetic resonance, and small angle X-ray scattering was used to observe and identify the structure and mode of action of the C. diff toxin. Believing that it was a binary toxin needing 2 components to function, researchers thought it could be similar to anthrax toxin, and sought to characterize what made the C. diff toxin different from anthrax.
"The most dangerous strains of C diff release a binary toxin that first binds to cells and then creates a pore-forming channel that allows the toxin to get inside and do harm," said Amedee de Georges, the study's principal investigator and a professor with the Advanced Science Research Center at The Graduate Center, CUNY's Structural Biology Initiative, in a press release.
Researchers also identified a calcium binding site on one of the C. diff toxin’s domains, which has not been identified on any similar toxins and suggests that calcium plays a critical role in regulating the formation and transition of C. diff into human cells, according to the study.
"We observed two similar but distinct forms of the C. diff toxin—one where we see the pore-forming channel and one where it is invisible," said Xingjian Xu, the paper’s first author and a Graduate Center, CUNY PhD student, in a press release. "This gives us clues as to how to prevent the formation of the channel and stop the bacteria from entering the cell."
Patients in health care facilities are increasingly at risk for acquiring C. diff due to the overuse of antibiotics, which has also made certain strains of the bacteria particularly difficult to treat. The disease affects roughly half a million people in the United States per year, and results in nearly 15,000 deaths in the United States annually.
Researchers identify starting point for designing drugs that cure Clostridium difficile [news release]. EurekAlert; January 2, 2020. Accessed March 10, 2021. https://www.eurekalert.org/pub_releases/2020-01/asrc-ris010220.php