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Iron transport-mediated drug delivery using mixed-ligand siderophore-beta-lactam conjugates
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
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.
Insights
Scientists developed novel mixed ligand siderophore-drug conjugates for enhanced iron uptake and drug delivery. These compounds bypass single-receptor resistance, improving microbial survival under iron-limited conditions.
Area of Science:
- Microbiology
- Biochemistry
- Drug Delivery
Background:
- Microbial iron assimilation is crucial for growth, relying on siderophores to chelate and transport iron via specific outer membrane receptors.
- Drug delivery can be facilitated by conjugating drugs to siderophores, but resistance often arises from mutations in these receptors.
- Previous strategies faced limitations due to single-point resistance mechanisms.
Purpose of the Study:
- To design and synthesize novel mixed ligand siderophore-drug conjugates capable of utilizing multiple iron uptake pathways.
- To overcome resistance mechanisms associated with single siderophore receptor deficiencies.
- To enhance the efficacy of iron-transport-mediated drug delivery in microbes.
Main Methods:
- Synthesis of mixed ligand siderophore-drug conjugates incorporating both hydroxamate and catechol moieties.
- Covalent linkage of carbacephalosporins as model drugs to the siderophore structures.
- Testing the assimilation of these conjugates by wild-type microbes and mutant strains lacking specific outer membrane receptors.
Main Results:
- Successfully synthesized mixed ligand siderophore-drug conjugates that chelate iron and deliver linked drugs.
- Demonstrated that these novel conjugates are assimilated via multiple active iron-transport processes.
- Observed effective uptake in both wild-type and mutant microbial strains with altered receptor profiles.
Conclusions:
- Mixed ligand siderophore-drug conjugates represent a new strategy for drug delivery, leveraging multiple iron uptake systems.
- This approach circumvents resistance mediated by single receptor mutations, as microbes require multiple receptors for efficient uptake.
- Microbial mutants resistant to these conjugates are likely to exhibit impaired iron uptake, leading to severe iron starvation and reduced viability.