Trunkfield, Amy E., Gurcha, Sudagar S., Besra, Gurdyal S. and Bugg, Tim. (2010) Inhibition of escherichia coli glycosyltransferase MurG and mycobacterium tuberculosis Gal transferase by uridine-linked transition state mimics. Bioorganic & Medicinal Chemistry, Vol.18 (No.7). pp. 2651-2663. ISSN 0968-0896

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Abstract

Glycosyltransferase MurG catalyses the transfer of N-acetyl-D-glucosamine to lipid intermediate I on the bacterial peptidoglycan biosynthesis pathway, and is a target for development of new antibacterial agents. A transition state mimic was designed for MurG, containing a functionalised proline, linked through the alpha-carboxylic acid, via a spacer, to a uridine nucleoside. A set of 15 functionalised prolines were synthesised, using a convergent dipolar cycloaddition reaction, which were coupled via either a glycine, proline, sarcosine, or diester linkage to the 5'-position of uridine. The library of 18 final compounds were tested as inhibitors of Escherichia coli glycosyltransferase MurG. Ten compounds showed inhibition of MurG at 1 mM concentration, the most active with IC50 400 mu M. The library was also tested against Mycobacterium tuberculosis galactosyltransferase GlfT2, and one compound showed effective inhibition at 1 mM concentration. (C) 2010 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology Q Science > QR Microbiology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Glycosyltransferases, Peptidoglycans -- Synthesis, Enzyme inhibitors, Mycobacterium tuberculosis, Escherichia coli
Journal or Publication Title:	Bioorganic & Medicinal Chemistry
Publisher:	Elsevier
ISSN:	0968-0896
Date:	April 2010
Volume:	Vol.18
Number:	No.7
Number of Pages:	13
Page Range:	pp. 2651-2663
Identification Number:	10.1016/j.bmc.2010.02.026
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Royal Society (Great Britain), Engineering and Physical Sciences Research Council (EPSRC), University of Warwick, Medical Research Council (Great Britain) (MRC), Wellcome Trust (London, England)
Grant number:	081569/Z/06/Z (WT)
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URI:	http://wrap.warwick.ac.uk/id/eprint/6174

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