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Antibiotics 2016, 5(1), 10; doi:10.3390/antibiotics5010010

Identification of a Fragment-Based Scaffold that Inhibits the Glycosyltransferase WaaG from Escherichia coli

1
Arrhenius Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm S-106 91, Sweden
2
Arrhenius Laboratory, Department of Organic Chemistry, Stockholm University, Stockholm S-106 91, Sweden
We would like to commemorate this work to Åke Wieslander who passed away in March 2013. We will always remember him as a great personality, devoted scientist and good spirited friend.
*
Authors to whom correspondence should be addressed.
Academic Editor: Waldemar Vollmer
Received: 26 November 2015 / Revised: 19 January 2016 / Accepted: 21 January 2016 / Published: 28 January 2016
(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)
View Full-Text   |   Download PDF [2871 KB, uploaded 28 January 2016]   |  

Abstract

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 14C-labeled UDP-glucose and LPS purified from a ∆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. View Full-Text
Keywords: glucosyltransferase; Gram-negative bacteria; lipopolysaccharide; fragment-based lead discovery; scaffold glucosyltransferase; Gram-negative bacteria; lipopolysaccharide; fragment-based lead discovery; scaffold
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Muheim, C.; Bakali, A.; Engström, O.; Wieslander, Å.; Daley, D.O.; Widmalm, G. Identification of a Fragment-Based Scaffold that Inhibits the Glycosyltransferase WaaG from Escherichia coli . Antibiotics 2016, 5, 10.

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