Oxidative activity of copper(II) complexes with aminoglycoside antibiotics as implication to the toxicity of these drugs

Abstract

The majority of aminoglycosidic antibiotics anchor Cu(II) ions by {NH 2, O-} chelates of the A and C rings of its molecule as distinct from amikacin, which belongs to the class of substituted ones. The results indicate that all these antibiotics effectively bind copper(II) at physiological pH. Cyclic voltammetry investigations and kinetic studies of H2O2 disproportionation and hydroxyl radicals detection made it possible to support the mechanism of oxidative reactivity of cupric complexes of aminoglycosides, which involves Cu(I) and Cu(III) redox states and metal-bound, rather than free radical species. The mechanism of this process appears to be complicated, and may have deleterious side-effects by leaking radical intermediates. The presence of these reactive oxygen species may be responsible for modulating the biological activity of these drugs. The interactions of copper(II) complexes of aminoglycosides with oxidation-susceptible biomolecules: 2'-deoxyguanosine, plasmid DNA and yeast tRNAPhe in both the presence and absence of hydrogen peroxide showed that the complexes with H2O2 are the most efficient oxidants, converting dG to its 8-oxo derivative, generating strand breaks in plasmid DNA and multiple cleavages in tRNAPhe. Some of these reactions may play a role in aminoglycoside-induced ototoxicity and nephrotoxicity; moreover, they may suggest that Cu(II)-aminoglycosides are potentially dangerous genotoxic agents. These complexes were also screened for their antibacterial activity and bioassays were engaged to find out the possibility of Cu(II)-kanamycin A complexes to induce tumor necrosis factor (TNF), interferon (IFN) and interleukin-10 (IL-10) in human peripheral blood leukocytes. The aim of these studies was to compare the biological action of antibiotic alone and complexed with copper(II) ions in both neutral and oxidative environment.