A number of different microorganisms have been demonstrated to bind various adhesive extracellular matrix proteins. These interactions seem to represent host tissue adhesion mechanisms which are crucial initial steps in the development of infection. The long range goal for this research program is to design inhibitors of the bacteria-fibronectin interaction which would prevent or reverse host tissue adherence and thereby the development of infection. A fibronectin receptor from Staphylococcus aureus has been isolated, the corresponding gene has been cloned and sequenced and peptides deduced from this nucleotide sequence have been shown to inhibit the binding of Staphylococcus aureus to fibronectin matrices. In the proposed studies, we will immunologically and functionally compare the isolated receptor with those obtained from other strains of S. aureus as well as from other species of staphylococci and streptococci. The amino acids in the S. aureus receptor essential for binding to fibronectin will be defined and small peptides synthesized which inhibit the binding of bacteria to fibronectin matrices. The interaction between receptors and fibronectin will be characterized in detail by x-ray crystallographic analyses of individual components as well as appropriate complexes. This will hopefully form the basis for the synthesis of new types of inhibitors. The virulence of fibronectin receptors will be determined by assaying transposon mutants which differ from the wild type cells only in fibronectin receptor activity. Fibronectin receptors will also be isolated, characterized and the corresponding genes cloned from different species of streptococci and coagulase negative staphylococci. Fibronectin binding sites in these receptors will be identified and synthetic peptides mimicking these sites will be tested for their ability to interfere with fibronectin binding. The effect of bacterial receptors on the normal behavior of eukaryotic cells, especially in terms of matrix assembly, will be analyzed.
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