Siderophore conjugates

The monobactams have a single beta-lactam ring structure. The only clinically used monobactam is aztreonam. Replacement of the 1-sulfonic acids residue in monobactam with an Af-sulphonylated carbonyl amino moiety yields monocarbams [71, 72 ]. So far, however, no monocarbam derivative is on the market, probably because their antimicrobial moiety is not optimal. Since micro-organisms need iron for growth, some siderophore-conjugated monocarbams are now under evaluation [73 ]. It is reasonable to assume that it will take some time until they are marketed. One of the many problems not yet solved is the in vivo fate of the siderophore itself, since it may create some new adverse effects of its own. 

Budzikiewicz H (2001) Siderophore-Antibiotic Conjugates used as Trojan Horses against Pseudomonas aeruginosa. Curr Top Med Chem 1 73... 

Ghosh A, Miller MJ (1993) Synthesis of Novel Citrate-Based Siderophores and Side-rophore-p iactam Conjugates. Iron Transport-mediated Dmg Delivery Systems. J Org Chem 58 7652... 

Similiar to albomycin and ferrichromes, the linear tripeptide of A -hydroxy-A -acetyl-ornithine can be used as the simplest chiral template for artificial siderophores. It can be used alone as a tripeptide like for 80, can be conjugated to a hydrophobic fatty acid 81132 pj. p j.j longer peptide 82, 83, and 85. ... 

The chemical nature of the linker, its size and buUciness will determine whether the drug remains attached to the siderophore or is released enzymatically into the cell. The synthesis of conjugates can proceed by derivatization of natural siderophores or by total synthesis. 

These conjugated natural antibiotics prompted the search for novel synthetic siderophores that contain a variety of drugs . 

Two distinct approaches can be envisioned in the development of siderophore-drug conjugates. A strategy of drug delivery utilizing the pathogen s own iron-transport system to act as a delivery system has been referred to as the Trojan Horse approach. Examples in which sulfonamides 194 , penicillins, cephalosporins and other antibiotics attached to DFO which exhibit antibacterial activity were reported. 

Siderophore drug conjugates can be utilized for both approaches. While the natural siderophores show generally low specificity, biomimetic analogs have been consistently improved to exhibit enhanced species specificity. 

The iron(III) complex of the microbial siderophore desferrioxamine B (DF, Fig. 16) was investigated as a MRI contrast agent [142],but the rapid injection of this agent may result in a precipitous drop in blood pressure [143]. For this reason, the primary amine on Fe-DF was conjugated with polyethylene-glycol to form Fe-PEG-DF (Fig. 16) [143, 144]. The new derivative has a Rj value of 1.35 mM-1 s-1 and R2 value of 1.67 mM-1 s 1 at 20 MHz and 37 °C, both values are similar to those of Fe-DF under the same conditions [143]. The LD50 for Fe-PEG-DF in mice is 7.7 mmol kg-1 and no blood pressure drops were observed after injection of Fe-PEG-DF. The enhancement of dog kidneys after injection of 0.2 mmol kg1 Fe-PEG-DF was similar to the enhancement profile caused by Gd-DTPA [143]. 

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