Application of Fragment-Based Screening to the Design of Inhibitors of Escherichia coli DsbA

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 avi...

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Published inAngewandte Chemie Vol. 127; no. 7; pp. 2207 - 2212
Main Authors 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.
Format Journal Article
LanguageEnglish
German
Published Weinheim WILEY-VCH Verlag 09.02.2015
WILEY‐VCH Verlag
Wiley Subscription Services, Inc
Subjects
Bacteria
Bacteriology
bakterielle Ansteckungskraft
Chemistry
Culture
E coli
Ecdsba
Escherichia coli
Fragment-basierte Wirkstoff-Forschung
Fragments
Inhibitors
Medizinische Chemie
Mutation
Proteins
Screening
Virulence
Wirkstoff-Design
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Summary: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. Kampfansage: DsbA ist ein Oxidoreduktase‐Enzym und von zentraler Bedeutung für die Virulenzentwicklung in E. coli. Ein Fragment‐basiertes Screening lieferte Verbindungen, welche die DsbA‐Aktivität in vitro und die E.‐coli‐Motilität in einem zellbasierten Assay hemmen. Kristallstrukturen dieser Verbindungen im Komplex mit DsbA liefern eine Erklärung für ihre Aktivität.
Bibliography:ark:/67375/WNG-3J4XJTMG-0
National Health and Medical Research Council - No. 1009785
We acknowledge funding from the National Health and Medical Research Council (grant number 1009785) and the Australian Research Council for an Australian Laureate Fellowship, a Future Fellowship, and a Discovery Early Career Researcher Award to J.L.M., B.H., and M.T., respectively (grant numbers FL0992138, FT130100580, and DE130101169). We thank the Bio21 Institute NMR Facility and the CSIRO Collaborative Crystallisation Centre (www.csiro.au/C3). This research was undertaken on the MX1 and MX2 beamlines at the Australian Synchrotron and at the UQ ROCX Diffraction Facility.
istex:92412263A3D917467C6A177ED82DA78CF34FA9DF
Australian Research Council
ArticleID:ANGE201410341
These authors contributed equally to this work.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201410341