The plague is one of the most feared infections in history because of its rapid ability to infect and its ability to cause severe illness and death. The disease is caused by the bacterium, Yersinia pestis, and since its discovery in 1896, has been the focus of significant attention. Since that time, the mechanisms of pathogenesis and virulence have been elucidated giving researchers the opportunity to find proper treatments ranging from antibiotics to blocking agents.
One of the hallmarks of Y. pestis infection, along with two other lesser pathogens, Y. pseudotuberculosis and Y. enterocolitica, is the production of a group of proteins known as the Yops (Yersinia outer proteins). Within this group is the most dangerous protein, YopH. It has the ability to prevent immune cells from engulfing the bacteria for destruction, prevents the release of toxic defense chemicals, and restricts the ability of these cells from sending chemical signals designed to call for backup. In essence, YopH leaves an immune cell defenseless allowing the bacterium to continue its campaign of disease.
Although the standard treatment for Yersinia is antibiotics, there have been reports of resistance to some of the go-to choices such as streptomycin. While the trouble is not quite as widespread as other pathogens, the risk for developing multi- and extremely resistant strains suggests other means to control infection should be sought. One such route is the inhibition of YopH such that the immune system can work effectively and clear the bacteria.
But finding inhibitors to YopH has not been an easy process. In 2003, one such option was found in the form of p-nitrocatechol sulfate. Around the same time, another candidate, aurintricarboxylic acid, was also found to have an inhibitory effect. Since then, a few other chemicals have been identified although none have proven to be entirely effective for use in humans.
That may soon change. A team of researchers from Poland and Canada may have come upon a natural source to combat YopH. In a study published last week, they describe the inhibitory effect of chicoric acid on the virulent protein and reveal it may be a possible source for help in times of dire need.
Chicoric acid was first discovered in 1958 in chicory plants and further analysis revealed it contained two caffeic acids. Since then, it has been found in a variety of other plants, such as echinacea, lettuce and basil. The plants produce this chemical to help fight off infections as well as heal wounds. In animals, there is evidence to suggest it has antioxidant and immune stimulatory activities including the process by which bacteria are engulfed for destruction. For the researchers, this appeared to be a good starting point.
But a hunch was not enough to conduct realistic studies in the lab. To achieve this, they had to go to the computer and perform a variety of analyses to see whether there was any affinity between YopH and chicoric acid. Indeed, there was. In fact, based on the analyses, the natural chemical might irreversibly block YopH suggesting a possible treatment.
At this point, the team went to the lab to test their computer-generated result. They didn’t use live bacteria but recombinant versions of YopH from Y enterocolitica. As expected, when chicoric acid was introduced, YopH was completely blocked from activity. When they tried to reverse the inactivation step, there was no return to activity. It was indeed irreversible.
When the authors examined the inhibition at the atomic level, they found chicoric acid not only blocked YopH but also changed its structure. They also realized there was another docking site on the protein, allowing for inhibition without direct blocking. This observation suggested there was not only direct blocking happening but a phenomenon known as allosteric inhibition in which a secondary site of attraction still leaves YopH with reduced or no activity.
The authors did not discuss the potential use of chicoric acid in the clinical setting however the results do provide a promising direction for treatment of Yersinia infections. As chicoric acid is a natural ingredient made from plants, it can be quickly harvested and should have little to no toxic impact on the human body. This could easily position it for animal and possibly human studies. In light of the rise of antibiotic resistance, it would be better to have this chemical in our arsenal to ensure we don’t end up having to face dire consequences in the future.
