Identification of ion-channel modulators that protect against aminoglycoside-induced hair-cell death

Kenyon, Emma J, Kirkwood, Nerissa K, Kitcher, Siân R, O'Reilly, Molly, Derudas, Marco, Cantillon, Daire M, Goodyear, Richard J, Secker, Abigail, Baxendale, Sarah, Bulley, James C, Waddell, Simon J, Whitfield, Tanya T, Ward, Simon E, Kros, Corné J and Richardson, Guy P (2017) Identification of ion-channel modulators that protect against aminoglycoside-induced hair-cell death. Journal of Clinical Investigation Insight, 2 (24). ISSN 2379-3708

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Aminoglycoside antibiotics are used to treat life-threatening bacterial infections, but can cause deafness due to hair-cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion channel modulators seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM1-43FX, decreased Texas Red conjugated neomycin labelling, or reduced neomycin-induced hair-cell death. After testing these 72 compounds, and six structurally-similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, six of which are permeant blockers of the hair-cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, five emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem.

Item Type: Article
Keywords: Aminoglycoside antibiotics, ototoxicity, hearing, deafness, mechano-electrical transduction, zebra fish neuromast, cochlear culture
Schools and Departments: Brighton and Sussex Medical School > Global Health and Infection
Brighton and Sussex Medical School > Neuroscience
School of Life Sciences > Chemistry
School of Life Sciences > Neuroscience
Research Centres and Groups: Sussex Drug Discovery Centre
Sussex Neuroscience
Wellcome Trust Brighton and Sussex Centre for Global Health Research
Subjects: Q Science > QP Physiology
Depositing User: Guy Richardson
Date Deposited: 06 Dec 2017 09:21
Last Modified: 22 Jan 2018 12:00

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Project NameSussex Project NumberFunderFunder Ref
Mechanisms of aminoglyscoside ototoxicity and drug damage repair in sensory hair cells: towards the design of otoprotective strategies.G1025MRC-MEDICAL RESEARCH COUNCILMR/K005561/1