title: Bromoenterobactins as potent inhibitors of a pathogen-associated, siderophore-modifying C-glycosyltransferase.
abstract: IroB is a C-glycosyltransferase encoded in the iroA cluster. C-Glucosylation of the bacterial siderophore enterobactin by IroB is a strategy some pathogenic bacteria use to evade the host's innate immunity mediated by lipocalin 2 (Lcn2). Without this modification, enterobactin can be tightly bound by host Lcn2, rendering it ineffective as a siderophore. Therefore, IroB inhibitors could be potential antibiotics against iroA-harboring pathogenic bacteria. We used enterobactin analogues to probe the properties of the active site of IroB and found that enterobactin analogues brominated at the C5 positions of the 2,3-dihydroxybenzoyl rings are potent inhibitors of IroB. This finding could lead to the discovery of effective antibiotics targeting iroA-containing bacteria.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hening
authors.initials: H
authors.lastname: Lin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gatto
authors.forename: David R
authors.initials: DR
authors.lastname: Liu
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
mesh_terms: D001966:Bromine / Q000737:chemistry*; D004758:Enterobactin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D017262:Siderophores / Q000737:chemistry / Q000494:pharmacology
chemical_list: D029968:Escherichia coli Proteins; D017262:Siderophores; D004758:Enterobactin; D005964:Glucosyltransferases; C497513:IroB protein, E coli; D001966:Bromine