title: Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids.
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, ΔtarS 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.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brown
authors.forename: Guoqing
authors.initials: G
authors.lastname: Xia
authors.forename: Lyly G
authors.initials: LG
authors.lastname: Luhachack
authors.forename: Jennifer
authors.initials: J
authors.lastname: Campbell
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Meredith
authors.forename: Calvin
authors.initials: C
authors.lastname: Chen
authors.forename: Volker
authors.initials: V
authors.lastname: Winstel
authors.forename: Cordula
authors.initials: C
authors.lastname: Gekeler
authors.forename: Javier E
authors.initials: JE
authors.lastname: Irazoqui
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002473:Cell Wall / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006031:Glycosylation; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016106:Methicillin Resistance / Q000502:physiology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology* / Q000235:genetics; D013682:Teichoic Acids / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D013682:Teichoic Acids; D047090:beta-Lactams; D016695:Glycosyltransferases