Iron transport-mediated drug delivery using mixed-ligand siderophore-beta-lactam conjugates.
BACKGROUND
Assimilation of iron is essential for microbial growth. Most microbes synthesize and excrete low molecular weight iron chelators called siderophores to sequester and deliver iron by active transport processes. Specific outer membrane proteins recognize, bind and initiate transport of species-selective ferric siderophore complexes. Organisms most often have specific receptors for multiple types of siderophores, presumably to ensure adequate acquisition of the iron that is essential for their growth. Conjugation of drugs to synthetic hydroxamate or catechol siderophore components can facilitate active iron-transport-mediated drug delivery. While resistance to the siderophore-drug conjugates frequently occurs by selection of mutants deficient in the corresponding siderophore-selective outer membrane receptor, the mutants are less able to survive under iron-deficient conditions and in vivo. We anticipated that synthesis of mixed ligand siderophore-drug conjugates would allow active drug delivery by multiple iron receptor recognition and transport processes, further reducing the likelihood that resistant mutants would be viable.


RESULTS
Mixed ligand siderophore-drug conjugates were synthesized by combining hydroxamate and catechol components in a single compound that could chelate iron, and that also contained a covalent linkage to carbacephalosporins, as representative drugs. The new conjugates appear to be assimilated by multiple active iron-transport processes both in wild type microbes and in selected mutants that are deficient in some outer membrane iron-transport receptors.


CONCLUSIONS
The concept of active iron-transport-mediated drug delivery can now be extended to drug conjugates that can enter the cell through multiple outer membrane receptors. Mutants that are resistant to such conjugates should be severely impaired in iron uptake, and therefore particularly prone to iron starvation.
Ghosh
A
A
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Ghosh
M
M
Niu
C
C
Malouin
F
F
Moellmann
U
U
Miller
M J
MJ
D000900:Anti-Bacterial Agents; D001419:Bacteria / Q000187:drug effects; D001425:Bacterial Outer Membrane Proteins; D001692:Biological Transport; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D018272:Porins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D017262:Siderophores / Q000138:chemical synthesis / Q000378:metabolism*; D047090:beta-Lactams / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D004364:Pharmaceutical Preparations; D018272:Porins; D011956:Receptors, Cell Surface; D017262:Siderophores; D047090:beta-Lactams; C035902:siderophore receptors; D007501:Iron