The emergence of bacteria resistant to almost all known antibiotics is one of the most important challenges for science. If no new prevention and treatment options for bacterial infectious are developed we may soon slip back into the state of the 19th century when people died of what we very recently thought of as trivial infections. In order to develop vaccines or treatments that differ significantly from drugs like penicillin we need to understand better the ways in which bacteria cause infections. To start with, bacteria have to gain a foothold in the human body. This is achieved through a variety of molecules present on the bacterial surface. These molecules, mostly proteins that often form hairlike structures, bind to human tissue at various sites in the body (e.g. throat, lung, guts, skin). An understanding of structure and function of these surface molecules is required for the development of vaccines. Also, if it was possible to prevent the bacteria from binding to the host, it would be possible to intervene with infections at an early stage. Streptococci are among the most common pathogens affecting humans and animals. Hundreds of millions of cases of strep throat are caused by the bacteria Streptococcus pyogenes every year. So far in countries with good health care penicillin treatment has been effective at keeping this common infection at bay. But as the sudden emergence of resistant pneumococci, C. difficile and MRSA has shown, we need to be prepared for the possibility of S. pyogenes developing penicillin resistance at any time (many strains are already resistant to various other drugs), which could have devastating consequences. For example, if not treated/treatable, strep throat can develop into life-threatening diseases such as rheumatic heart disease (RHD). Despite penicillin availability, RHD is one of the biggest killers of children and youths in India and other developing nations. In RHD our immune system turns against proteins in the body and destroys tissue of the heart valves. This devastating effect is only poorly understood but is known to be linked to a family of proteins (called M proteins) that cover the bacteria in what under the microscope looks like a furry coat. M proteins were discovered over 80 years ago, and were quickly realised to be required by streptococci for causing disease. Despite their abundance and obvious importance our understanding of how they function is very limited. This lack of progress can be explained with the unusual properties of M proteins, which make them difficult subjects for conventional molecular investigations. We have shown that significant progress can be made using a combination of complementary powerful biophysical techniques (NMR and EPR) that will reveal, at the level of atoms, what M proteins look like and how they work. In this project we will specifically investigate the binding of M proteins to the most abundant human protein, collagen. Collagen is found throughout the body, and its abundance makes it a particularly attractive target for bacteria, and may aid in establishing an infection. Importantly, bacterial binding to collagen may also be the underlying cause of RHD, since collagen is the main component of heart valve tissue. Intriguingly, there are similarities between rheumatic diseases caused by bacterial infections and common autoimmune diseases such as rheumatoid arthritis. The causes of rheumatoid arthritis are unknown but it has been suggested that bacterial infection may play a role. Therefore, our research may uncover interesting links between bacterial infections and other diseases. A molecular understanding of M proteins can be considered central to the problem of research into streptococcal diseases. Our investigations will ultimately contribute to the development of urgently required new drugs or vaccines for one of the most important and dangerous infectious agents.