Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1021/cb500988r

Type

Journal article

Journal

ACS Chem Biol

Publication Date

17/04/2015

Volume

10

Pages

957 - 964

Keywords

Anti-Bacterial Agents, Bacterial Proteins, Cysteine, Disulfides, Drug Design, Drug Evaluation, Preclinical, Escherichia coli Proteins, Humans, Inhibitory Concentration 50, Lysine, Membrane Proteins, Protein Disulfide-Isomerases, Small Molecule Libraries, Structure-Activity Relationship, Thioredoxins, Ubiquinone