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.

Highly chelating stellate mesoporous silica nanoparticles for specific iron removal from biological media

“…The supernatants were then analyzed using UV-visible absorption spectrophotometry. An excess of free DFoB was added to the supernatant to ensure complete complexation of the unreacted FeNTA and the corresponding Fe(III) concentrations were evaluated from the absorbance measurement at 430 nm (LMCT absorption band of FeDFoB at 430 nm, ε 430 = 2950 M -1 •cm -1 ) 7 .…”

“…However, in our experimental conditions (HEPES buffer at 50 mM), the FeNTA absorption was markedly altered by another more intense absorption at about 210 nm (linked to HEPES) which prevents the accurate determination of the iron content (FigureS4.A). To overcome this problem and analyze FeNTA supernatants, free DFoB was added to the supernatant, which rapidly led to the formation of FeDFoB complex which is characterized by a Ligand-to-Fe(III) charge transfer band (i.e., LMCT) of moderate intensity centered at 430 nm (ε 430 = 2950 M -1 •cm -1 )53 . The color changes from light yellow to orange, confirming the exchange of the ligands and the formation of the FeDFoB complex.…”

Metal self-assembly mimosine peptides with enhanced antimicrobial activity: towards a new generation of multitasking chelating agents

“…petrobactin), but more in-depth studies aimed at understanding the mechanism of action are needed for supporting this hypothesis. The siderophore mimicking property of mimosine peptides could be applied for diagnostic and theragnostic treatment of bacterial infections, 76 while mimosine is structurally similar to that of DFP and could form stable complexes with Gd(III) 77 and other lanthanide metals. 37 Mimosine based peptides are structurally and functionally different from classical antibiotics and their MIC activity should be compared with AMPs rather than antibiotics.…”

Synthetic transport systems in bacteria

“…Among the tested cargo molecules in this study were the Boc protecting group, cyclohexane, naphthalene, phenylmethylbenzene groups, coumarin and the antibiotic ciprofloxacin. In earlier studies it was demonstrated that the siderophores ferrichrome, ferrioxamine and pyochelin can be used to deliver fluorophores into the cytoplasm of Pseudomonas strains and Yersinia enterocolitica [66][67][68][69][70].…”