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Identification of a Fragment-Based Scaffold that Inhibits the Glycosyltransferase WaaG from Escherichia coli dagger
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 6
2016 (English)In: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 5, no 1Article in journal (Refereed) Published
Abstract [en]

WaaG is a glycosyltransferase that is involved in the biosynthesis of lipopolysaccharide in Gram-negative bacteria. Inhibitors of WaaG are highly sought after as they could be used to inhibit the biosynthesis of the core region of lipopolysaccharide, which would improve the uptake of antibiotics. Herein, we establish an activity assay for WaaG using C-14-labeled UDP-glucose and LPS purified from a increment waaG strain of Escherichia coli. We noted that addition of the lipids phosphatidylglycerol (PG) and cardiolipin (CL), as well as the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) increased activity. We then use the assay to determine if three molecular scaffolds, which bind to WaaG, could inhibit its activity in vitro. We show that 4-(2-amino-1,3-thiazol-4-yl)phenol inhibits WaaG (IC50 1.0 mM), but that the other scaffolds do not. This study represents an important step towards an inhibitor of WaaG by fragment-based lead discovery.

Place, publisher, year, edition, pages
2016. Vol. 5, no 1
Keyword [en]
lipopolysaccharide, glucosyltransferase, Gram-negative bacteria, scaffold, fragment-based lead discovery
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:su:diva-129989DOI: 10.3390/antibiotics5010010ISI: 000373607800003OAI: oai:DiVA.org:su-129989DiVA: diva2:928006
Available from: 2016-05-13 Created: 2016-05-09 Last updated: 2016-07-06Bibliographically approved

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Muheim, ClaudioDaley, Daniel O.Widmalm, Göran
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Department of Biochemistry and BiophysicsDepartment of Organic Chemistry
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