The neurotransmitter norepinephrine (NE) stimulates the growth of low inocula of Escherichia coli in a minimal medium (SAPI) supplemented with serum (SAPI؉serum) and induces the production of an "autoinducer" (AI) which, in turn, promotes E. coli growth in the absence of NE. Given the importance of NE, epinephrine, and their corresponding adrenergic agonists and antagonists in clinical medicine, we sought to investigate the molecular basis for these observations. Using a variety of NE precursors, metabolites, and therapeutic agents, we demonstrated that their ability to stimulate E. coli growth in SAPI؉serum is dependent on the presence of a catechol (1,2-dihydroxybenzene) moiety with maximal activity requiring a two-carbon substituent incorporating a terminal primary amine. Serum contains the iron-binding glycoprotein, transferrin, and when SAPI؉serum was supplemented with sufficient Fe 3؉ to saturate transferrin, growth inhibition was relieved. Other metal cations, including Mg 2؉ , Ca 2؉ , and Zn 2؉ , had no effect. These data suggested that the stimulation of E. coli growth by NE in SAPI؉serum may involve the catecholate siderophore, enterobactin, a cyclic triester of 2,3-dihydroxybenzoylserine. Consistent with this hypothesis, E. coli strains with mutations in ferrienterobactin transport (fepA or tonB) or enterobactin biosynthesis (entA) did not respond to NE. Furthermore, NE induced expression of the ferrienterobactin receptor, FepA, during growth in SAPI؉serum. The enterobactin degradation product, 2,3-dihydroxybenzoylserine (DBS) was as effective as NE in stimulating the growth of E. coli and mutations in fepA or tonB abolished the DBS-dependent growth stimulation. In contrast to NE, however, DBS stimulated the growth of the entA mutant. Moreover, after growth in an ironlimited M9 medium in the absence of NE, ethyl acetate extracts of the E. coli entA ؉ parent but not of the entA mutant contained AI, i.e., stimulated the growth of E. coli in SAPI؉serum. Taken together, these data show that when low numbers of E. coli are inoculated into SAPI؉serum, NE, DBS, and related catecholamines induce the enterobactin iron uptake system. This, in turn, facilitates iron sequestration from transferrin and indicates that the AI present in NE-conditioned SAPI؉serum medium is enterobactin and its DBS breakdown products. Bacterial cells undergo a wide variety of physiological and morphological adaptations in response to chemical and physical changes in their environment. From the prokaryotic perspective, the successful interaction of bacterial cells with mammalian host tissues depends not only on a coordinated response to environmental cues such as nutrient availability, population density, temperature, osmolarity and pH (37, 56) but also on diverse host cell effector molecules. In general, the influence of host signaling molecules on bacteria has received relatively little attention (25). However, hormones such as epinephrine (12) and insulin (57), the neurotransmitter norepinephrine (NE [34]), and cytokines such as int...