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Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA
journal contributionposted on 2023-05-18, 05:37 authored by Adams, LA, Sharma, P, Mohanty, B, Ilyichova, OV, Mulcair, MD, Williams, ML, Gleeson, EC, Totsika, M, Doak, BC, Caria, S, Rimmer, K, Henry HorneHenry Horne, Shouldice, SR, Vazirani, M, Headey, SJ, Plumb, BR, Martin, JL, Heras, B, Simpson, JS, Scanlon, MJ
The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in a diverse range of substrates in the periplasm of Gram-negative bacteria. DsbA substrates include proteins that play a role 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. We have used a biophysical screening approach to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro and produce a phenotype that is consistent with inhibition of DsbA in a cell based assay. 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.
Publication titleAngewandte Chemie
PublisherWiley-V C H Verlag Gmbh
Place of publicationPo Box 10 11 61, Weinheim, Germany, D-69451
Rights statementCopyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim