title: 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.affiliation: From the Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry and.
authors.forename: Eli
authors.initials: E
authors.lastname: Shulman
authors.forename: Valery
authors.initials: V
authors.lastname: Belakhov
authors.forename: Gao
authors.initials: G
authors.lastname: Wei
authors.forename: Ann
authors.initials: A
authors.lastname: Kendall
authors.forename: Esther G
authors.initials: EG
authors.lastname: Meyron-Holtz
authors.forename: Dorit
authors.initials: D
authors.lastname: Ben-Shachar
authors.forename: Jochen
authors.initials: J
authors.lastname: Schacht
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003051:Cochlea / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D030342:Genetic Diseases, Inborn / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D010101:Oxygen Consumption / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D024101:Mitochondrial Proteins; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species
keywords: Aminoglycosides; Antibiotics Action; Cytoplasmic Protein Synthesis Inhibition; Genetic Diseases; Mitochondrial Apoptosis; Mitochondrial Protein Synthesis Inhibition; Ototoxicity; Oxidative Stress; Ribosome Function