Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 46, Pages 18909-18914Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1209126109
Keywords
PBP2A; antibiotic resistance; beta lactam potentiation; murein; WTA glycosylation
Categories
Funding
- National Institutes of Health [1R01AI099144, P01AI083214, T32AI007061]
- German Research Council [TRR34, SFB766]
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Staphylococcus aureus peptidoglycan (PG) is densely functionalized with anionic polymers called wall teichoic acids (WTAs). These polymers contain three tailoring modifications: D-alanylation, alpha-O-GlcNAcylation, and beta-O-GlcNAcylation. Here we describe the discovery and biochemical characterization of a unique glycosyltransferase, TarS, that attaches beta-O-GlcNAc (beta-O-N-acetyl-D-glucosamine) residues to S. aureus WTAs. We report that methicillin resistant S. aureus (MRSA) is sensitized to beta-lactams upon tarS deletion. Unlike strains completely lacking WTAs, which are also sensitive to beta-lactams, Delta tarS strains have no growth or cell division defects. Because neither alpha-O-GlcNAc nor beta-O-Glucose modifications can confer resistance, the resistance phenotype requires a highly specific chemical modification of the WTA backbone, beta-O-GlcNAc residues. These data suggest beta-O-GlcNAcylated WTAs scaffold factors required for MRSA resistance. The beta-O-GlcNAc transferase identified here, TarS, is a unique target for antimicrobials that sensitize MRSA to beta-lactams.
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