title: Peptide inhibitors of the Escherichia coli DsbA oxidative machinery essential for bacterial virulence.
abstract: One approach to address antibiotic resistance is to develop drugs that interfere with bacterial virulence. A master regulator of virulence in Gram-negative bacteria is the oxidative folding machinery comprising DsbA and DsbB. A crystal structure at 2.5 Å resolution is reported here for Escherichia coli DsbA complexed with PFATCDS, a heptapeptide derived from the partner protein Escherichia coli DsbB. Details of the peptide binding mode and binding site provide valuable clues for inhibitor design. Structure-activity relationships for 30 analogues were used to produce short peptides with a cysteine that bind tightly to EcDsbA (Kd = 2.0 ± 0.3 μM) and inhibit its activity (IC50 = 5.1 ± 1.1 μM). The most potent inhibitor does not bind to or inhibit human thioredoxin that shares a similar active site. This finding suggests that small molecule inhibitors can be designed to exploit a key interaction of EcDsbA, as the basis for antivirulence agents with a novel mechanism of action.
authors.affiliation: Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Wilko
authors.initials: W
authors.lastname: Duprez
authors.forename: Lakshmanane
authors.initials: L
authors.lastname: Premkumar
authors.forename: Maria A
authors.initials: MA
authors.lastname: Halili
authors.forename: Fredrik
authors.initials: F
authors.lastname: Lindahl
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
mesh_terms: D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010084:Oxidation-Reduction; D010455:Peptides / Q000494:pharmacology*; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014774:Virulence
chemical_list: D029968:Escherichia coli Proteins; D010455:Peptides; D019704:Protein Disulfide-Isomerases; C526648:dsbA protein, E coli