ArticleThe Journal of biological chemistry2014
Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 110 citations in OpenAlex.
- Identification of small molecules that enhance aminoglycoside-mediated suppression ofMolecular therapy. Oncology · 2026Article
- Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.Archives of toxicology · 2026Review
- Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.bioRxiv : the preprint server for biology · 2024Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease.Cell stem cell · 2024Article
- Insights into the molecular underlying mechanisms and therapeutic potential of endoplasmic reticulum stress in sensorineural hearing loss.Frontiers in molecular neuroscience · 2024Review
- Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.Frontiers in neurology · 2024Article
- Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process.PLoS biology · 2023Article
- Pharmaceuticals Promoting Premature Termination Codon Readthrough: Progress in Development.Biomolecules · 2023Review
- Balancing Nonsense Mutation Readthrough and Toxicity of Designer Aminoglycosides for Treatment of Genetic Diseases.ACS medicinal chemistry letters · 2023Article
- The synthetic aminoglycoside ELX-02 induces readthrough of G550X-CFTR producing superfunctional protein that can be further enhanced by CFTR modulators.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- Triamterene Functions as an Effective Nonsense Suppression Agent for MPS I-H (Hurler Syndrome).International journal of molecular sciences · 2023Article
- Recoding of Nonsense Mutation as a Pharmacological Strategy.Biomedicines · 2023Review
- Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells.Frontiers of medicine · 2022Article
- Ataluren suppresses a premature termination codon in an MPS I-H mouse.Journal of molecular medicine (Berlin, Germany) · 2022Article
- Multifunctional Redox Modulators Protect Auditory, Visual, and Cognitive Function.Antioxidants & redox signaling · 2022Article
- Identifying targets to prevent aminoglycoside ototoxicity.Molecular and cellular neurosciences · 2022Review
- NanoLuc reporters identifyiScience · 2022Article
- Tetrandrine Prevents Neomycin-Induced Ototoxicity by Promoting Steroid Biosynthesis.Frontiers in bioengineering and biotechnology · 2022Article
- Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review.JAC-antimicrobial resistance · 2021Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.