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Crystal structure of the antibiotic albomycin in complex with the outer membrane transporter FhuA

Published online by Cambridge University Press:  01 May 2000

ANDREW D. FERGUSON
Affiliation:
Fachbereich Biologie, Universität Konstanz, M656, Postfach 55 60, D-78457 Konstanz, Germany Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec H3A 2B4, Canada
VOLKMAR BRAUN
Affiliation:
Lehrstuhl Mikrobiologie/Membranphysiologie, Universität Tübingen, Auf der Morgenstelle 28, D-72076 Tübingen, Germany
HANS-PETER FIEDLER
Affiliation:
Lehrstuhl Mikrobiologie/Biotechnologie, Universität Tübingen, Auf der Morgenstelle 28, D-72076 Tübingen, Germany
JAMES W. COULTON
Affiliation:
Fachbereich Biologie, Universität Konstanz, M656, Postfach 55 60, D-78457 Konstanz, Germany
KAY DIEDERICHS
Affiliation:
Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec H3A 2B4, Canada
WOLFRAM WELTE
Affiliation:
Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec H3A 2B4, Canada
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Abstract

One alternative method for drug delivery involves the use of siderophore-antibiotic conjugates. These compounds represent a specific means by which potent antimicrobial agents, covalently linked to iron-chelating siderophores, can be actively transported across the outer membrane of Gram-negative bacteria. These “Trojan Horse” antibiotics may prove useful as an efficient means to combat multi-drug–resistant bacterial infections. Here we present the crystallographic structures of the natural siderophore-antibiotic conjugate albomycin and the siderophore phenylferricrocin, in complex with the active outer membrane transporter FhuA from Escherichia coli. To our knowledge, this represents the first structure of an antibiotic bound to its cognate transporter. Albomycins are broad-host range antibiotics that consist of a hydroxamate-type iron-chelating siderophore, and an antibiotically active, thioribosyl pyrimidine moiety. As observed with other hydroxamate-type siderophores, the three-dimensional structure of albomycin reveals an identical coordination geometry surrounding the ferric iron atom. Unexpectedly, this antibiotic assumes two conformational isomers in the binding site of FhuA, an extended and a compact form. The structural information derived from this study provides novel insights into the diverse array of antibiotic moieties that can be linked to the distal portion of iron-chelating siderophores and offers a structural platform for the rational design of hydroxamate-type siderophore-antibiotic conjugates.

Type
Research Article
Copyright
2000 The Protein Society

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