Kenyon, E.J., Kirkwood, N.K., Kitcher, S.R. et al. (14 more authors) (2021) Identification of a novel series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity. JCI Insight, 6 (7). e145704. ISSN 2379-3708
Abstract
To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics we screened 10,240 compounds, selecting those that protected against neomycin and gentamicin in zebrafish lateral-line hair cells and, when retested in mouse cochlear cultures, prevented gentamicin-induced death of outer hair cells (OHCs). Of 64 compounds that protected zebrafish hair cells, 8 protect OHCs from gentamicin in vitro. These hits share structural features and all block, to varying degrees, the OHC’s mechano-electrical transducer (MET) channel, a known route of aminoglycoside entry into hair cells. Further characterisation of one of the strongest MET-channel blockers, UoS-7692, revealed it additionally protects against kanamycin and tobramycin, and does not abrogate the bactericidal activity of gentamicin. UoS-7692 behaves, like the aminoglycosides, as a permeant blocker of the MET channel, significantly reduces gentamicin-Texas Red loading into OHCs, and preserves lateral-line function in neomycin-treated zebrafish. Trans-tympanic injection of UoS-7692 protects mouse OHCs from furosemide-kanamycin exposure in vivo and partially preserves hearing. The results confirm the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides, and provide a series of hit compounds that will inform the design of future otoprotectants.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021, Kenyon et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. (http://creativecommons.org/licenses/by/4.0/) |
Keywords: | Drug screens; Mouse models; Neuroscience; Therapeutics |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Funding Information: | Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/J003050/1 BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/S007008/1 Medical Research Council MC_G0802527 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 01 Apr 2021 16:35 |
Last Modified: | 14 Apr 2021 16:09 |
Status: | Published |
Publisher: | American Society for Clinical Investigation |
Refereed: | Yes |
Identification Number: | 10.1172/jci.insight.145704 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:172629 |
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Licence: CC-BY 4.0