Streptococcus gordonii is one of the more than 700 different species of bacteria that live in the mouth. But when it spreads to the heart via the bloodstream, it can cause infective endocarditis, which means unwanted blood clots on the heart valves. Even with treatment, mortality can range up to 30%. The University of Bristol, though, has uncovered the mechanism that may lead to the disease—with an eye on new treatment that may be able to fight it.
Using a giant x-ray microscope, its researchers visualized the structure and dynamics of a protein called CshA. Previous studies by the university found that CshA plays a role in how the bacterium targets heart tissue. Now, the researchers have found that CshA acts like a “molecular lasso” that binds S gordonii to the surface of human cells. This adhesion is among the first steps of the bacterium’s ability to cause disease.
“What our work has revealed is a completely new mechanism by which S gordonii and related bacteria are able to bind to human tissues,” said Catherine Back, PhD, of Bristol’s School of Oral and Dental Sciences and lead author of the study. “We have named this the ‘catch-clamp’ mechanism.”
The terminal portion of CshA is very flexible, which means it can be cast out from the surface of the bacterium like a lasso. When the lasso contacts fibronectin on the surface of human cells (the “catch”), it brings CshA and fibronectin into close proximity. This then enables another portion of CshA to tightly “clamp” the 2 proteins together, anchoring S gordonii to the host cell surface.
“What is particularly exciting about this work is that it opens up new possibilities for designing molecules that inhibit either the catch or the clamp steps in this process, or potentially both,” said co-researcher Paul Race, PhD, of Britsol’s School of Biochemistry and the BrisSynBio Research Centre. “The latter possibility is particularly intriguing, as bacteria are generally less likely to become resistant to agents that target multiple steps in an infective process.”
“With the molecular insight that our study provides, it is now a realistic possibility that we can begin to develop anti-adhesive agents that target disease-causing Streptococcus and related bacteria,” said Angela Nobbs, PhD, of Bristol’s School of Oral and Dental Sciences.
The study, “The Streptococcus Gordonii Adhesin CshA Binds Host Fibronectin Via a Catch-Clamp Mechanism,” was published by the Journal of Biological Chemistry.
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