A novel target for therapeutics against Staphylococcus
Staphylococcus aureus is a common pathogen that can cause a range of diseases from mild skin infections to life-threatening sepsis in humans. Some surface proteins on S. aureus play important roles in the disease process. One of these bacterial surface proteins is clumping factor A (ClfA) that binds to the C-terminal region of one of the three chains of fibrinogen (Fg), a blood protein that plays a key role in coagulation. New research has uncovered how S. aureus interacts with the blood coagulation protein fibrinogen in methicillin-resistant Staphylococcus aureus (MRSA) infections, a finding that could aid in developing therapeutics against this potentially deadly disease.
Once occurring mostly in healthcare facilities but now affecting segments of the general population, MRSA is a bacterial pathogen responsible for a range of diseases from mild skin infection to life-threatening sepsis. Even with antibiotics, these infections can still be fatal. Researchers carried out biochemical and structural studies to determine the binding mechanism of clumping factor A (ClfA), a surface protein that plays an important role in the pathogenesis of S. aureus. The group found that ClfA binds to the blood-clotting protein fibrinogen (Fg) at a site that is also responsible for inducing platelet activation and thrombosis (a clot inside a blood vessel). The results show significant structural differences in how staphylococcal and platelet receptor proteins recognize fibrinogen. By exploiting this difference in recognition, the researchers show that agents could be designed that inhibit the ClfA–Fg interaction but do not interfere with the interaction of Fg with the platelet integrin, therefore avoiding unwanted side effects on the circulatory system. This opens the field for the design of a novel class of anti-staph therapeutics.
A Structural Model of the Staphylococcus aureus ClfA–Fibrinogen Interaction Opens New Avenues for the Design of Anti-Staphylococcal Therapeutics. 2008 PLoS Pathog 4(11): e1000226
The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) c-chain. ClfA is the major virulence factor responsible for the observed clumping of S. aureus in blood plasma and has been implicated as a virulence factor in a mouse model of septic arthritis and in rabbit and rat models of infective endocarditis. We report here a high-resolution crystal structure of the ClfA ligand binding segment in complex with a synthetic peptide mimicking the binding site in Fg. The residues in Fg required for binding to ClfA are identified from this structure and from complementing biochemical studies. Furthermore, the platelet integrin aIIbb3 and ClfA bind to the same segment in the Fg c-chain but the two cellular binding proteins recognize different residues in the common targeted Fg segment. Based on these differences, we have identified peptides that selectively antagonize the ClfA-Fg interaction. The ClfA-Fg binding mechanism is a variant of the “Dock, Lock and Latch” mechanism previously described for the Staphylococcus epidermidis SdrG–Fg interaction. The structural insights gained from analyzing the ClfANFg peptide complex and identifications of peptides that selectively recognize ClfA but not aIIbb3 may allow the design of novel antistaphylococcal agents. Our results also suggest that different MSCRAMMs with similar structural organization may have originated from a common ancestor but have evolved to accommodate specific ligand structures.
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Tags: Bacteria, Biology, Health, Medicine, Microbiology, Science
