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

Adams, Luke A., Sharma, Pooja, Mohanty, Biswaranjan, Ilyichova, Olga V., Mulcair, Mark D., Williams, Martin L., Gleeson, Ellen C., Totsika, Makrina, Doak, Bradley C., Caria, Sofia, Rimmer, Kieran, Horne, James, Shouldice, Stephen R., Vazirani, Mansha, Headey, Stephen J., Plumb, Brent R., Martin, Jennifer L., Heras, Begoña, Simpson, Jamie S., & Scanlon, Martin J. (2015) Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA. Angewandte Chemie (International Edition), 54(7), pp. 2179-2184.

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Abstract

The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram-negative bacteria. DsbA substrates include proteins involved 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. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. 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.

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6 citations in Scopus
9 citations in Web of Science®
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ID Code: 85958
Item Type: Journal Article
Refereed: Yes
DOI: 10.1002/anie.201410341
ISSN: 1433-7851
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Funding:
Copyright Owner: Copyright 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Deposited On: 23 Jul 2015 22:39
Last Modified: 26 Jul 2015 23:07

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