Aminoglycosides are highly potent, broad-spectrum antibiotics with many desirable properties for the treatment of life-threatening infections. However aminoglycosides use is highly restricted due to the complications attributable to their nephro- and ototoxicities. Nephrotoxic effects are most common and are developed after relatively short period of treatment. In many cases these effects are reversible if administration is discontinued. However ototoxic effects induced by aminoglycosides usually result in irreversible apopoptosis of auditory and vestibular sensory cells. Aminoglycosides induced toxicity probably results from a combination of different factors/mechanisms such as interactions with phospholipids, inhibition of phospholipases and the formation of free radicals. The later mechanism, aminoglycosides-induced formation of free radicals, has received strong support as the underlying cause of ototoxicity because antioxidants and iron chelators attenuate aminoglycoside-induced hearing loss. These observations point to a key role of mitochondria involved in iron metabolism as well as a major source of reactive oxygen species (ROS) as a target of ototoxic aminoglycosides. To test this hypothesis, we have developed a methodology in order to study the mitochondrial translation inhibition caused by aminoglycosides by using either intact mitochondria derived from human cells, or selectively in human cells.
The observed results demonstrate following general features of aminoglycosides: 1) aminoglycosides that are potent antibiotics are also strong inhibitors of mitochondrial protein synthesis; 2) reduced inhibition of mitochondrial protein synthesis correlates with reduced toxicity; 3) the new class of aminoglycosides developed in our group for the treatment of genetic diseases (NB compounds) were very poor inhibitors of mitochondrial protein synthesis and subsequently exhibit poor cell toxicity. The impact of aminoglycosides induced mitochondrial protein synthesis on cell respiration and apoptosis due to formation of reactive oxygen radicals, free Fe(II) and subsequent Fenton reaction will be discussed.
