Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 54, Issue 4, Pages 1580-1589Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01158-09
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- Technische Universitat Munchen
- DFG [MI 1265/1-1]
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L-norepinephrine (NE) is a neuroendocrine catecholamine that supports bacterial growth by mobilizing iron from a primary source such as holotransferrin to increase its bioavailability for cellular uptake. Iron complexes of NE resemble those of bacterial siderophores that are scavenged by human neutrophil gelatinase-associated lipocalin ( NGAL) as part of the innate immune defense. Here, we show that NGAL binds iron-complexed NE, indicating physiological relevance for both bacterial and human iron metabolism. The fluorescence titration of purified recombinant NGAL with the Fe-III center dot (NE)(3) iron complex revealed high affinity for this ligand, with a K-D of 50.6 nM. In contrast, the binding protein FeuA of Bacillus subtilis, which is involved in the bacterial uptake of triscatecholate iron complexes, has a K-D for Fe-III center dot (NE)(3) of 1.6 mu M, indicating that NGAL is an efficient competitor. Furthermore, NGAL was shown to inhibit the NE-mediated growth of both E. coli and B. subtilis strains that either are capable or incapable of producing their native siderophores enterobactin and bacillibactin, respectively. These experiments suggest that iron-complexed NE directly serves as an iron source for bacterial uptake systems, and that NGAL can function as an antagonist of this iron acquisition process. Interestingly, a functional FeuABC uptake system was shown to be necessary for NE-mediated growth stimulation as well as its NGAL-dependent inhibition. This study demonstrates for the first time that human NGAL not only neutralizes pathogen-derived virulence factors but also can effectively scavenge an iron-chelate complex abundant in the host.
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