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ACS Chem Biol. 2015 Apr 17;10(4):957-64. doi: 10.1021/cb500988r. Epub 2015 Jan 27.

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

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†Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
‡Department of Chemistry, South Parks Road, Oxford OX1 3QZ, United Kingdom.
§Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.


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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