Abstract
During an inflammatory response in the gut, some commensal bacteria such as E. coli can thrive and contribute to disease. Here we demonstrate that enterobactin (Ent), a catecholate siderophore released by E. coli, is a potent inhibitor of myeloperoxidase (MPO), a bactericidal enzyme of the host. Glycosylated Ent (salmochelin) and non-catecholate siderophores (yersiniabactin and ferrichrome) fail to inhibit MPO activity. An E. coli mutant (ΔfepA) that overproduces Ent, but not an Ent-deficient double mutant (ΔaroB/ΔfepA), inhibits MPO activity and exhibits enhanced survival in inflamed guts. This survival advantage is counter-regulated by lipocalin 2, a siderophore-binding host protein, which rescues MPO from Ent-mediated inhibition. Spectral analysis reveals that Ent interferes with compound I [oxoiron, Fe(IV)=O] and reverts the enzyme back to its native ferric [Fe(III)] state. These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage.
Highlights
During an inflammatory response in the gut, some commensal bacteria such as E. coli can thrive and contribute to disease
Microbiotal dysbiosis is commonly observed in several types of inflammatory bowel diseases (IBDs)
IBD is associated with a bloom in bacterial species belonging to the family Enterobacteriaceae, class
Summary
During an inflammatory response in the gut, some commensal bacteria such as E. coli can thrive and contribute to disease. We demonstrate that enterobactin (Ent), a catecholate siderophore released by E. coli, is a potent inhibitor of myeloperoxidase (MPO), a bactericidal enzyme of the host. An E. coli mutant (DfepA) that overproduces Ent, but not an Ent-deficient double mutant (DaroB/DfepA), inhibits MPO activity and exhibits enhanced survival in inflamed guts. This survival advantage is counter-regulated by lipocalin 2, a siderophore-binding host protein, which rescues MPO from Ent-mediated inhibition. Spectral analysis reveals that Ent interferes with compound I [oxoiron, Fe(IV) 1⁄4 O] and reverts the enzyme back to its native ferric [Fe(III)] state These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage. Our study describes a novel mechanism that promotes survival and growth of E. coli, a well-known opportunistic pathogen in a variety of chronic intestinal diseases associated with microbiotal dysbiosis
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