title: Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA.
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.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia) http://www.pharm.monash.edu.au.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Adams
authors.forename: Pooja
authors.initials: P
authors.lastname: Sharma
authors.forename: Biswaranjan
authors.initials: B
authors.lastname: Mohanty
authors.forename: Olga V
authors.initials: OV
authors.lastname: Ilyichova
authors.forename: Mark D
authors.initials: MD
authors.lastname: Mulcair
authors.forename: Martin L
authors.initials: ML
authors.lastname: Williams
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Gleeson
authors.forename: Makrina
authors.initials: M
authors.lastname: Totsika
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Doak
authors.forename: Sofia
authors.initials: S
authors.lastname: Caria
authors.forename: Kieran
authors.initials: K
authors.lastname: Rimmer
authors.forename: James
authors.initials: J
authors.lastname: Horne
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Shouldice
authors.forename: Mansha
authors.initials: M
authors.lastname: Vazirani
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Headey
authors.forename: Brent R
authors.initials: BR
authors.lastname: Plumb
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
authors.forename: Begoña
authors.initials: B
authors.lastname: Heras
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Simpson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D019704:Protein Disulfide-Isomerases; C526648:dsbA protein, E coli
keywords: EcDsbA; bacterial virulence; drug design; fragment-based drug discovery; medicinal chemistry