Abstract
A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). 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 EcDsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (6), 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 EcDsbA. Binding affinity was calculated based on NMR studies and compounds 25 and 28 were identified as the highest affinity binders with dissociation constants (KD) of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of EcDsbA inhibitors.
Highlights
The rise of multidrug-resistant bacteria has rendered many of our current antibiotics ineffective.With few antibacterial drugs in the development pipeline, antibiotic resistance has been identified as a significant global health threat, highlighting the urgent need for new classes of antibacterial drugs with novel mechanisms of action
We focus on elaboration of benzofuran fragment hits identified in the screen using a structure-guided approach
This site was amenable to coupling reactions to extend the fragment from the benzene ring of the benzofuran moiety and introduce a range of functionalities to probe for favourable interactions with residues in the EcDsbA binding site
Summary
The rise of multidrug-resistant bacteria has rendered many of our current antibiotics ineffective.With few antibacterial drugs in the development pipeline, antibiotic resistance has been identified as a significant global health threat, highlighting the urgent need for new classes of antibacterial drugs with novel mechanisms of action. Bacteria rely on the biosynthesis of virulence factors to establish an infection in a host and cause disease. Many of these virulence factors, such as secreted toxins and surface proteins, require folding into their native state by the thiol-disulfide oxidoreductase enzyme. The loss of functional DsbA in Gram-negative bacteria generally leads to attenuated virulence, increased sensitivity to antibiotics, and reduced fitness in animal models of infection [2,3,4,5,6]. Chemical inhibition of DsbA represents an attractive approach to attenuate bacterial virulence and could potentially lead to the development of novel antibacterial therapeutics [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
