Modular synthesis of diphospholipid oligosaccharide fragments of the bacterial cell wall and their use to study the mechanism of moenomycin and other antibiotics |
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Authors: | Gampe Christian M Tsukamoto Hirokazu Wang Tsung-Shing Andrew Walker Suzanne Kahne Daniel |
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Affiliation: | a Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138, USA b Harvard Medical School, Department of Microbiology and Molecular Genetics, Boston, MA 02115, USA |
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Abstract: | We present a flexible, modular route to GlcNAc-MurNAc-oligosaccharides that can be readily converted into peptidoglycan (PG) fragments to serve as reagents for the study of bacterial enzymes that are targets for antibiotics. Demonstrating the utility of these synthetic PG substrates, we show that the tetrasaccharide substrate lipid IV (3), but not the disaccharide substrate lipid II (2), significantly increases the concentration of moenomycin A required to inhibit a prototypical PG-glycosyltransferase (PGT). These results imply that lipid IV and moenomycin A bind to the same site on the enzyme. We also show the moenomycin A inhibits the formation of elongated polysaccharide product but does not affect length distribution. We conclude that moenomycin A blocks PG-strand initiation rather than elongation or chain termination. Synthetic access to diphospholipid oligosaccharides will enable further studies of bacterial cell wall synthesis with the long-term goal of identifying novel antibiotics. |
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Keywords: | Lipid IV Moenomycin Peptidoglycan Transglycosylation Carbohydrate synthesis |
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