Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases.

Abstract

There is compelling evidence that aminoglycoside (AG) antibiotics can induce the mammalian ribosome to suppress disease-causing nonsense mutations and partially restore the expression of functional proteins. However, prolonged AG treatment can cause detrimental side effects in patients, including most prominently, ototoxicity. Recent mechanistic discussions have considered the relative contributions of mitochondrial and cytoplasmic protein synthesis inhibition to AG-induced ototoxicity. We show that AGs inhibit mitochondrial protein synthesis in mammalian cells and perturb cell respiration, leading to a time- and dose-dependent increase in superoxide overproduction and accumulation of free ferrous iron in mitochondria caused by oxidative damage of mitochondrial aconitase, ultimately leading to cell apoptosis via the Fenton reaction. These deleterious effects increase with the increased potency of AG to inhibit the mitochondrial rather than cytoplasmic protein synthesis, which in turn correlates with their ototoxic potential in both murine cochlear explants and the guinea pig in vivo. The deleterious effects of AGs were alleviated in synthetic derivatives specially designed for the treatment of genetic diseases caused by nonsense mutations and possessing low affinity toward mitochondrial ribosomes. This work highlights the benefit of a mechanism-based drug redesign strategy that can maximize the translational value of "readthrough therapy" while mitigating drug-induced side effects. This approach holds promise for patients suffering from genetic diseases caused by nonsense mutations.

• Authors: Eli Shulman, Valery Belakhov, Gao Wei, Ann Kendall, Esther G Meyron-Holtz, Dorit Ben-Shachar, Jochen Schacht, Timor Baasov
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 4 Pg. 2318-30 (Jan 24 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24302717 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoglycosides
• Mitochondrial Proteins
• Protein Synthesis Inhibitors
• Reactive Oxygen Species

Topics

• Aminoglycosides (adverse effects, pharmacology)
• Animals
• Apoptosis (drug effects)
• Cochlea (metabolism)
• Cytoplasm (metabolism)
• Dose-Response Relationship, Drug
• Genetic Diseases, Inborn (drug therapy, genetics, metabolism)
• Guinea Pigs
• HeLa Cells
• Humans
• Mice
• Mitochondria (metabolism)
• Mitochondrial Proteins (biosynthesis)
• Oxygen Consumption (drug effects)
• Protein Biosynthesis (drug effects)
• Protein Synthesis Inhibitors (adverse effects, pharmacology)
• Reactive Oxygen Species (metabolism)
• Ribosomes (metabolism)