title: Ferrioxamine B analogues: targeting the FoxA uptake system in the pathogenic Yersinia enterocolitica.
abstract: A series of ferrioxamine B analogues that target the bacterium Yersinia enterocolitica were prepared. These iron carriers are composed of three hydroxamate-containing monomeric units. Two identical monomers consist of N-hydroxy-3-aminopropionic acid coupled with beta-alanine, and a third unit at the amino terminal is composed of N-hydroxy-3-aminopropionic acid and one of the following amino acids: beta-alanine (1a), phenylalanine (1b), cyclohexylalanine (1c), or glycine (1d). Thermodynamic results for representatives of the analogues have shown a strong destabilization (3-4 orders of magnitude) of the ferric complexes with respect to ferrioxamine B, probably due to shorter spacers and a more strained structure around the metal center. No significant effect of the variations at the N-terminal has been observed on the stability of the ferric complexes. By contrast, using in vivo radioactive uptake experiments, we have found that these modifications have a substantial effect on the mechanism of iron(III) uptake in the pathogenic bacteria Yersinia enterocolitica. Analogues 1a and 1d were utilized by the ferrioxamine B uptake system (FoxA), while 1b and 1c either used different uptake systems or were transported to the microbial cell nonspecifically by diffusion via the cell membrane. Transport via the FoxA system was also confirmed by uptake experiments with the FoxA deficient strain of Yersinia enterocolitica. A fluorescent marker, attached to 1a in a way that did not interfere with its biological activity, provided additional means to monitor the uptake mechanism by fluorescence techniques. Of particular interest is the observation that 1a was utilized by the uptake system of ferrioxamine B in Yersinia enterocolitica (FoxA) but failed to use the ferrioxamine uptake route in Pseudomonas putida. Here, we present a case in which biomimetic siderophore analogues deliberately designed for a particular bacterium can distinguish between related uptake systems of different microorganisms.
authors.affiliation: Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Kornreich-Leshem
authors.forename: Carmit
authors.initials: C
authors.lastname: Ziv
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Gumienna-Kontecka
authors.forename: Rina
authors.initials: R
authors.lastname: Arad-Yellin
authors.forename: Yona
authors.initials: Y
authors.lastname: Chen
authors.forename: Mourad
authors.initials: M
authors.lastname: Elhabiri
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Albrecht-Gary
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Hadar
authors.forename: Abraham
authors.initials: A
authors.lastname: Shanzer
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D002942:Circular Dichroism; D003676:Deferoxamine / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D005290:Ferric Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D007504:Iron Radioisotopes / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017262:Siderophores / Q000737:chemistry / Q000378:metabolism; D015008:Yersinia enterocolitica / Q000187:drug effects / Q000378:metabolism*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics
chemical_list: D001425:Bacterial Outer Membrane Proteins; D005290:Ferric Compounds; C489524:FoxA protein, bacteria; D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D011956:Receptors, Cell Surface; D017262:Siderophores; D015091:beta-Alanine; C002577:ferrioxamine B; D003676:Deferoxamine