Title |
Small Molecule Inhibitors of Disulfide Bond Formation by the Bacterial DsbA–DsbB Dual Enzyme System
|
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Published in |
ACS Chemical Biology, January 2015
|
DOI | 10.1021/cb500988r |
Pubmed ID | |
Authors |
Maria A. Halili, Prabhakar Bachu, Fredrik Lindahl, Chérine Bechara, Biswaranjan Mohanty, Robert C. Reid, Martin J. Scanlon, Carol V. Robinson, David P. Fairlie, Jennifer L. Martin |
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. |
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