ArticleThe Journal of clinical investigation2015
Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 85 citations in OpenAlex.
- Comparison of the efficacy of carbapenems and cephalosporins for postoperative treatment of perforated appendicitis in children.World journal of gastrointestinal surgery · 2025Article
- Inhibition of GABARAP or GABARAPL1 prevents aminoglycoside- induced hearing loss.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Aminoglycoside induces RIPOR2 translocation and phosphatidylserine externalization via distinct mechanisms.Frontiers in cellular neuroscience · 2025Article
- Endolymphatic hydrops and cochlear synaptopathy after noise exposure are distinct sequelae of hair cell stereociliary bundle trauma.Scientific reports · 2024Article
- Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.bioRxiv : the preprint server for biology · 2024Article
- Hyperosmotic sisomicin infusion: a mouse model for hearing loss.Scientific reports · 2024Article
- Role of Memantine in Limiting Cochleotoxicity in Rats.Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India · 2024Article
- Hyperosmotic Sisomicin Infusion: A Mouse Model for Hearing Loss.Research square · 2024Article
- Article
- Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.Frontiers in neurology · 2024Article
- Ototoxicity: a high risk to auditory function that needs to be monitored in drug development.Frontiers in molecular neuroscience · 2024Review
- Aminoglycosides-Related Ototoxicity: Mechanisms, Risk Factors, and Prevention in Pediatric Patients.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Selection of viral capsids and promoters affects the efficacy of rescue ofMolecular therapy. Methods & clinical development · 2023Article
- Synthesis of Gentamicins C1, C2, and C2a and Antiribosomal and Antibacterial Activity of Gentamicins B1, C1, C1a, C2, C2a, C2b, and X2.ACS infectious diseases · 2023Article
- Aminoglycoside-Related Nephrotoxicity and Ototoxicity in Clinical Practice: A Review of Pathophysiological Mechanism and Treatment Options.Advances in therapy · 2023Review
- AAV-Net1 facilitates the trans-differentiation of supporting cells into hair cells in the murine cochlea.Cellular and molecular life sciences : CMLS · 2023Article
- RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss.Developmental cell · 2022Article
- ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death.Journal of molecular medicine (Berlin, Germany) · 2022Article
- Identifying targets to prevent aminoglycoside ototoxicity.Molecular and cellular neurosciences · 2022Review
- In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum β lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.
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