Small molecule inhibitors of disulfide bond formation by the bacterial DsbA-DsbB dual enzyme system

Halili, Maria A., Bachu, Prabhakar, Lindahl, Fredrik, Bechara, Cherine, Mohanty, Biswaranjan, Reid, Robert C., Scanlon, Martin, Robinson, Carol V., Fairlie, David P. and Martin, Jennifer L. (2015) Small molecule inhibitors of disulfide bond formation by the bacterial DsbA-DsbB dual enzyme system. ACS Chemical Biology, 10 4: 957-964. doi:10.1021/cb500988r


Author Halili, Maria A.
Bachu, Prabhakar
Lindahl, Fredrik
Bechara, Cherine
Mohanty, Biswaranjan
Reid, Robert C.
Scanlon, Martin
Robinson, Carol V.
Fairlie, David P.
Martin, Jennifer L.
Title Small molecule inhibitors of disulfide bond formation by the bacterial DsbA-DsbB dual enzyme system
Journal name ACS Chemical Biology   Check publisher's open access policy
ISSN 1554-8929
1554-8937
Publication date 2015-01-20
Year available 2015
Sub-type Article (original research)
DOI 10.1021/cb500988r
Open Access Status
Volume 10
Issue 4
Start page 957
End page 964
Total pages 8
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2016
Language eng
Formatted abstract
The DsbA:DsbB redox machinery catalyzes disulfide bond formation in secreted proteins and is required for bacterial virulence factor assembly. Both enzymes have been identified as targets for antivirulence drugs. Here, we report synthetic analogues of ubiquinone (dimedone derivatives) that inhibit disulfide bond formation (IC50 ∼ 1 μM) catalyzed by E. coli DsbA:DsbB. The mechanism involves covalent modification of a single free cysteine leaving other cysteines unmodified. A vinylogous anhydride in each inhibitor is cleaved by the thiol, which becomes covalently modified to a thioester by a propionyl substituent. Cysteines and lysines on DsbA and DsbB and a nonredox enzyme were modified in a manner that implies some specificity. Moreover, human thioredoxin was not inhibited under the same conditions that inhibited EcDsbA. This proof of concept work uses small molecules that target specific cysteines to validate the DsbA and DsbB dual enzyme system as a viable and potentially druggable antivirulence target.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 14 Apr 2015, 10:51:33 EST by Susan Allen on behalf of Institute for Molecular Bioscience