Attachment of microorganisms to host tissues is regarded as the crucial initial step in the pathogenesis of microbial infections. Staphylococcus aureus is a major bacterial pathogen that can cause a range of diseases from mild skin infections to life-threatening sepsis in humans. Following entry into the circulation, S. aureus expresses a family of surface protein adhesins that mediate the adherence of the organism to extracellular matrix (ECM) components of the host. Many adhesins from staphylococci, including clumping factor A (ClfA) and ClfB, are known to contain minisatellite SDR (serine-aspartate repeats) that converts host fibrinogen to fibrin and promotes its agglutination with fibrin fibrils, thereby shielding bacteria from immune defenses. In addition, it has been found that GlcNAc modification of SDR proteins prevents degradation by human neutrophil cathepsin G and safeguards staphylococcal adhesion to host tissues. This specific modification on SDR-proteins also promotes S. aureus replication in the bloodstream of mammalian hosts. Very recently, it was demonstrated that two novel glycosyltransferases (GTs), SdgA and SdgB, modify all SDR-proteins by an ordered mechanism, with SdgB appending the sugar residues proximal to the target SDR, followed by additional modification by SdgA. Among all the identified GTs, SdgB and SdgA are the most homologous to each other (43% identity; 63% similarity), comprising an N-terminal domain of unknown function and a core catalytic domain with GT-B fold. However, the lack of structural information, particularly about the N-terminal domain, has been a major impediment to elucidating the molecular mechanism and developing inhibitors against these unique GTs. In current study, we will use X-ray crystallographic and other biophysical methods to investigate these virulence factors in S. aureus.
|Effective start/end date||8/1/15 → 7/31/16|
- serine-aspartate repeats
- virulence factor
- X-ray Crystallography
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