Bromoenterobactins as potent inhibitors of a pathogen-associated, siderophore-modifying C-glycosyltransferase.
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.
Lin
Hening
H
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Fischbach
Michael A
MA
Gatto
Gregory J
GJ
Liu
David R
DR
Walsh
Christopher T
CT
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
D029968:Escherichia coli Proteins; D017262:Siderophores; D004758:Enterobactin; D005964:Glucosyltransferases; C497513:IroB protein, E coli; D001966:Bromine