| Summary: | A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from <i>Escherichia coli</i> (<i>Ec</i>DsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to <i>Ec</i>DsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (<b>6</b>), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of <i>Ec</i>DsbA. Binding affinity was calculated based on NMR studies and compounds <b>25</b> and <b>28</b> were identified as the highest affinity binders with dissociation constants (<i>K</i><sub>D</sub>) of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of <i>Ec</i>DsbA inhibitors.
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