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

One alternative method for drug delivery involves the use of siderophore-an tibiotic conjugates. These compounds represent a specific means by which po tent antimicrobial agents, covalently linked to iron-chelating siderophores . can be actively transported across the outer membrane of Gram-negative ba cteria. These "Trojan Horse" antibiotics may prove useful as an efficient m eans to combat multi-drug-resistant bacterial infections. Here we present t he crystallographic structures of the natural siderophore-antibiotic conjug ate albomycin and the siderophore phenylferricrocin. in complex with the ac tive outer membrane transporter FhuA from Escherichia coli. To our knowledg e, this represents the first structure of an antibiotic bound to its cognat e 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 si derophores, the three-dimensional structure of albomycin reveals an identic al coordination geometry surrounding the ferric iron atom. Unexpectedly, th is antibiotic assumes two conformational isomers in the binding site of Fhu A, an extended and a compact form. The structural information derived from this study provides novel insights into the diverse array of antibiotic moi eties that can be linked to the distal portion of iron-chelating siderophor es and offers a structural platform for the rational design of hydroxamate- type siderophore-antibiotic conjugates.