The human mouth can have more than 700 different species of bacteria. Under normal circumstances these microbes co-exist as part of our resident oral microbiota but when they spread to other tissues via the blood stream, the results can be catastrophic.
Researchers from the University of Bristol have revealed a potentially key molecular process that occurs in the case of infective endocarditis, a type of cardiovascular disease in which bacteria cause unwanted blood clots to form on heart valves. If untreated, this condition is fatal and even with treatment, mortality rates are high. There are over 2,000 cases of infective endocarditis in the United Kingdom (UK) annually and the amount is rising.
The research involved the use of the UK national synchrotron facility, Diamond Light Source. Using this giant X-ray microscope the team was able to visualise the structure and dynamics of a protein called CshA which was believed to play an important role in targeting the oral bacterium Streptococcus gordonii to the tissues of the heart. The researchers were intrigued to find that CshA acts as a ‘molecular lasso’ to enable S. gordonii to bind to the surface of human cells. Such adhesive interactions are critical first steps in the ability of this bacterium to cause disease. The researchers discovered a new mechanism by which S. gordonii and related bacteria are able to bind to human tissues, called the ‘catch-clamp’ mechanism.
The team was able to demonstrate that the terminal portion of CshA is very flexible. This allows it to 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 two proteins together, anchoring S. gordonii to the host cell surface.
The researchers believe that new molecules could be designed to inhibit either or both of the ‘catch’ or the ‘clamp’ steps in the process. The researchers believe it is now possible to develop anti-adhesive agents that target disease-causing Streptococcus and related bacteria.
Catherine R. Back, Maryta N. Sztukowska, Marisa Till, Richard J. Lamont, Howard F. Jenkinson, Angela H. Nobbs, Paul R. Race. The Streptococcus gordonii Adhesin CshA Protein Binds Host Fibronectin via a Catch-Clamp Mechanism. Journal of Biological Chemistry, 2017; 292 (5): 1538.