• Wojciech Lesniak slimus_2000@yahoo.com

Background

Gentamicin (fig. 1) is one of the aminoglycosides, an important group of antibiotics frequently used against bacterial infection, especially in severe sepsis. They kill bacteria by inhibition of the translation step in microbal protein synthesis and subsequently damaging the cytoplasmic membrane. A major disadvantage of gentamicin common to aminoglycosides is its auditiory- and nephro-toxicity.

Fig 1. Drawing of the structure of gentamicin.

Role of Transition Metals

Copper complexes of kanamycin [5, 6] and amikacin [7], existing at physiological pH are very effective mediators of oxidative damage to DNA, RNA and other biomolecules, via reactive oxygen species formation. These processes may become a important element of cellular toxicity of aminoglycosides.

On the other hand gentamicin has been shown to bind iron, forming low spin Fe(II)-gentamicin and both low and high Fe(III)-gentamicin complexes [8]. The postulated iron binding site which yields the low spin Fe(II)-gentamicin 1:2 complex is composed of two amine nitrogens and a connecting glycoside oxygen. Iron coordination through this proposed binding site may be key to aminoglycoside toxicity, as previously postulated to result from gentamicin free radical formation via iron complex [9]. However, gentamicin has several distinct potential binding sites for metal ions that can be strong chelators for Cu(II) ions as well.

In order to gain deeper knowledge of the role of metal ions in biological activity of aminoglycoside antibiotics, the binding ability of gentamicin towards iron and copper ions as well as structure and reactivity of resulting complexes have to be studied.

References

[1] M. Jezowska-Bojczuk, W. Bal, J. Chem. Soc. Dalton Trans., 1998 153-159.
[2] Jezowska-Bojczuk, W. Bal, H. Kozlowski, Inorg. Chim. Acta, 1998, 275/276, 541.
[3] M. Jezowska-Bojczuk, A. Karaczyn, W. Bal, J. Inorg. Biochem., 1998, 71, 129.
[4] M. Jezowska-Bojczuk, A. Karaczyn, H. Kozlowski, Carbohydr. Res., 1998, 313, 265.
[5] A. Sreedhara, and J. A. Cowan, Chem. Commun., 1998, 1737.
[6] A. Sreedhara, Patwardhan, and J. A. Cowan, Chem. Commun., 1999, 1147.
[7] E. M. Priuska, K. Clark-Baldwin, V. Pecoraro, J. Schacht, Inorg. Chim. Acta., 1998, 273, 85.
[8] Priuska, E. M., and Schacht, J. Biochem. Pharmacol., 1995, 50, 1749.

Recent Project Publications (1995-present)

• Journals, Periodicals, and Books:
  • Lesniak, W.; Harris, W.R.; Yudenfreund Kravitz, J.; Schacht, J.; Pecoraro, V.L. "The Solution Chemistry of Copper(II)-Gentamicin Complexes: Relevance to Metal," Inorg. Chem., 2003 , 42, 1420-1429