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Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA

Citation

Adams, LA and Sharma, P and Mohanty, B and Ilyichova, OV and Mulcair, MD and Williams, ML and Gleeson, EC and Totsika, M and Doak, BC and Caria, S and Rimmer, K and Horne, H and Shouldice, SR and Vazirani, M and Headey, SJ and Plumb, BR and Martin, JL and Heras, B and Simpson, JS and Scanlon, MJ, Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA, Angewandte Chemie, 54, (7) pp. 2179-2184. ISSN 1433-7851 (2014) [Refereed Article]

Copyright Statement

Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Official URL: http://dx.doi.org/2015 Wiley-VCH Verlag GmbH & Co....

DOI: doi:10.1002/anie.201410341

Abstract

The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in a diverse range of substrates in the periplasm of Gram-negative bacteria. DsbA substrates include proteins that play a role in bacterial virulence. In the absence of DsbA many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. We have used a biophysical screening approach to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro and produce a phenotype that is consistent with inhibition of DsbA in a cell based assay. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence.

Item Details

Item Type:Refereed Article
Keywords:bacterial virulence, drug design, EcDsbA, fragment-based drug discovery, medicinal chemistry
Research Division:Medical and Health Sciences
Research Group:Medical Microbiology
Research Field:Medical Bacteriology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Infectious Diseases
Author:Horne, H (Dr James Horne)
ID Code:97111
Year Published:2014
Web of Science® Times Cited:10
Deposited By:Central Science Laboratory
Deposited On:2014-12-03
Last Modified:2015-08-03
Downloads:0

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