Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity

Kenyon, Emma J., Kirkwood, Nerissa K., Kitcher, Siân R., Goodyear, Richard J., Derudas, Marco, Cantillon, Daire M., Baxendale, Sarah, de la Vega de León, Antonio, Mahieu, Virginia N., Osgood, Richard T., Wilson, Charlotte Donald, Bull, James C., Waddell, Simon J., Whitfield, Tanya T., Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377, Kros, Corné J. and Richardson, Guy P. 2021. Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity. JCI Insight 6 (7) , e145704. 10.1172/jci.insight.145704

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Abstract

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics, 10,240 compounds were initially screened in zebrafish larvae, selecting for those that protected lateral-line hair cells against neomycin and gentamicin. When the 64 hits from this screen were retested in mouse cochlear cultures, 8 protected outer hair cells (OHCs) from gentamicin in vitro without causing hair-bundle damage. These 8 hits shared structural features and blocked, to varying degrees, the OHC’s mechano-electrical transducer (MET) channel, a route of aminoglycoside entry into hair cells. Further characterization of one of the strongest MET channel blockers, UoS-7692, revealed it additionally protected against kanamycin and tobramycin and did not abrogate the bactericidal activity of gentamicin. UoS-7692 behaved, like the aminoglycosides, as a permeant blocker of the MET channel; significantly reduced gentamicin–Texas red loading into OHCs; and preserved lateral-line function in neomycin-treated zebrafish. Transtympanic injection of UoS-7692 protected mouse OHCs from furosemide/kanamycin exposure in vivo and partially preserved hearing. The results confirmed 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Additional Information:	This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Date of First Compliant Deposit:	30 July 2021
Date of Acceptance:	18 March 2021
Last Modified:	04 May 2023 04:22
URI:	https://orca.cardiff.ac.uk/id/eprint/143049

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