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Infection and Immunity, November 2002, p. 5913-5923, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.5913-5923.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Growth Response of Escherichia coli to Neurotransmitters and Related Catecholamine Drugs Requires a Functional Enterobactin Biosynthesis and Uptake System

Claire L. Burton,1 Siri Ram Chhabra,2 Simon Swift,1,{dagger} Tom J. Baldwin,1,2 Helen Withers,1,2 Stephen J. Hill,3 and Paul Williams1,2*

Institute of Infections and Immunity,1 Institute of Cell Signalling, Queens Medical Centre, University of Nottingham, Nottingham NG7 2UH,3 School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom2

Received 17 January 2002/ Returned for modification 15 May 2002/ Accepted 24 July 2002

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 Fe3+ to saturate transferrin, growth inhibition was relieved. Other metal cations, including Mg2+, Ca2+, and Zn2+, 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 iron-limited 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.

* Corresponding author. Mailing address: Institute of Infections and Immunity, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom. Phone: 44-115-9515047. Fax: 44-115-8466296. E-mail: paul.williams{at}nottingham.ac.uk.

Editor: V. J. DiRita

{dagger} Present address: Division of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Infection and Immunity, November 2002, p. 5913-5923, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.5913-5923.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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