Abstract
Staphylococcus aureus peptidoglycan (PG) is densely functionalized with anionic polymers called wall teichoic acids (WTAs). These polymers contain three tailoring modifications: d -alanylation, α- O -GlcNAcylation, and β- O -GlcNAcylation. Here we describe the discovery and biochemical characterization of a unique glycosyltransferase, TarS, that attaches β- O -GlcNAc (β- O - N -acetyl- d -glucosamine) residues to S. aureus WTAs. We report that methicillin resistant S. aureus (MRSA) is sensitized to β-lactams upon tarS deletion. Unlike strains completely lacking WTAs, which are also sensitive to β-lactams, Δ tarS strains have no growth or cell division defects. Because neither α- O -GlcNAc nor β- O -Glucose modifications can confer resistance, the resistance phenotype requires a highly specific chemical modification of the WTA backbone, β- O -GlcNAc residues. These data suggest β- O -GlcNAcylated WTAs scaffold factors required for MRSA resistance. The β- O -GlcNAc transferase identified here, TarS, is a unique target for antimicrobials that sensitize MRSA to β-lactams.
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