Hidden Mode of Action of Glycopeptide Antibiotics: Inhibition of Wall Teichoic Acid Biosynthesis.

Glycopeptide antibiotics inhibit the peptidoglycan biosynthesis in Gram-positive bacteria by targeting lipid II. This prevents the recycling of bactoprenol phosphate, the lipid transporter that is shared by peptidoglycan and wall teichoic acid biosyntheses. In this study, we investigate the effects of glycopeptide antibiotics on peptidoglycan and wall teichoic acid biosynthesis. The incorporation of d-[1-13C]alanine, d-[15N]alanine, and l-[1-13C]lysine into peptidoglycan and wall teichoic acid in intact whole cells of Staphylococcus aureus was measured using 13C{15N} and 15N{13C} rotational-echo double resonance NMR. S. aureus treated with oritavancin and vancomycin at subminimal inhibitory concentrations exhibit a large reduction in d-Ala incorporation into wall teichoic acid, but without changes to the peptidoglycan cross-links or the stem-links. Thus, sequestration of bactoprenol phosphate by glycopeptide antibiotics resulted in inhibition of d-Ala incorporation into the wall teichoic acid prior to the inhibition of peptidoglycan biosynthesis. Our finding shows that S. aureus responds to glycopeptide-induced cell wall stress by routing all available d-Ala to the peptidoglycan biosynthesis, at the cost of reducing the wall teichoic acid biosynthesis.