Application of Fragment‐Based Screening to the Design of Inhibitors of Escherichia coli DsbA |
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Authors: | Dr Luke A Adams Dr Pooja Sharma Dr Biswaranjan Mohanty Olga V Ilyichova Dr Mark D Mulcair Dr Martin L Williams Ellen C Gleeson Dr Makrina Totsika Dr Bradley C Doak Dr Sofia Caria Dr Kieran Rimmer Dr James Horne Dr Stephen R Shouldice Mansha Vazirani Dr Stephen J Headey Brent R Plumb Prof Jennifer L Martin Dr Begoña Heras Dr Jamie S Simpson Dr Martin J Scanlon |
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Institution: | 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au;2. School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072 (Australia);3. Present address: Institute of Health and Biomedical, Innovation, Queensland University of Technology, Kelvin Grove, QLD 4059 (Australia);4. Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072 (Australia);5. Present address: La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086 (Australia) |
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Abstract: | The thiol‐disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram‐negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell‐based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence. |
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Keywords: | bacterial virulence drug design EcDsbA fragment‐based drug discovery medicinal chemistry |
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