Introduction
Aminoglycosides are a class of antibiotics that have been used in the clinical setting for more than half a century. They are commonly used to treat various bacterial infections and are considered as broad-spectrum antibiotics. However, their clinical applications are limited due to their severe side effects, including nephrotoxicity, ototoxicity, and neuromuscular blockade. To improve their therapeutic efficacy and minimize their toxicity, researchers have developed aminoglycoside conjugates by attaching them to various molecules, including carbohydrates, peptides, and iron. In this article, we will focus on aminoglycoside conjugates with iron, particularly aminoglycoside-iron complexes, also known as aminoglycoside-iron chelates, or amino acid-chelated iron, or amino acid-iron complexes, or amino acid chelates containing iron, or simply, iron-amino acid chelates.
Function and Action of Aminoglycoside-Iron Complexes
The aminoglycoside-iron complexes have shown interesting biological properties due to their dual targeting capability. The aminoglycoside moiety targets bacteria by binding to the bacterial 16S ribosomal RNA, thereby interfering with bacterial protein synthesis and causing bacterial cell death. The iron moiety, on the other hand, targets mammalian cells, these cells express transferrin receptors on their surface, which bind to transferrin with high affinity, enabling transferrin to transport iron across the cell membrane and into the cells.
The aminoglycoside-iron complexes are assumed to work in two ways:
They can act as prodrugs, releasing iron when they encounter transferrin receptors and thus delivering iron to the cells without causing toxic effects to the cells;
They can bind to bacterial 16S ribosomal RNA and simultaneously deliver iron to the bacteria, directly causing bacterial lysis through synergistic effects.
Chelation and Stability of Aminoglycoside-Iron Complexes
The formation of aminoglycoside-iron complexes is based on the chelation of the iron ion by the amino acid residues present in the aminoglycoside molecule. In general, amino acids have side chains with different functional groups, such as amino (-NH2), carboxyl (-COOH), hydroxyl (-OH), and sulfhydryl (-SH) groups, which can coordinate with the iron ion and stabilize the complex.
The stability of aminoglycoside-iron complexes depends on the nature of the amino acid residue used and the pH conditions of the environment. The most common amino acids used for chelating iron ions are histidine, aspartic acid, and glutamic acid. They have been demonstrated to form highly stable chelates with iron ions at neutral pH. The stability of the complexes increases with the increase in the number of amino acid residues involved in chelation and with the increase in the binding constant of the amino acid residue to the iron ion.
Interactions between Aminoglycoside-Iron Complexes and Other Molecules
The aminoglycoside-iron complexes can interact with other molecules, such as proteins, lipids, and nucleic acids. The interactions can affect the biological properties of the complexes and lead to changes in their functions and actions.
Aminoglycoside-iron complexes have shown to interact preferentially with serum albumin, the most abundant protein in blood plasma. The interaction between the complexes and albumin can affect their pharmacokinetics and biodistribution, as albumin is known to play a key role in drug transport and delivery.
Moreover, lipids can also interact with the aminoglycoside-iron complexes, leading to their incorporation into cell membranes. The incorporation can result in altered membrane properties and increased membrane permeability, thus promoting cellular uptake of the complexes.
Finally, the interaction between aminoglycoside-iron complexes and DNA has also been studied. The complexes have been shown to bind to DNA and cause DNA damage, thus providing a potential mechanism for their antimicrobial activity.
Conclusion
In conclusion, aminoglycoside-iron complexes are an emerging class of compounds that show great potential in the treatment of bacterial infections. The complexes combine the antibacterial activity of the aminoglycoside with the beneficial effects of iron, resulting in dual-targeting capabilities and limited side effects. Future studies should focus on optimizing the design and synthesis of aminoglycoside-iron complexes to enhance their stability, efficacy, and safety.
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