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

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.

SUBMITTER: Kenyon EJ

PROVIDER: S-EPMC8133782 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Kenyon Emma J EJ Kirkwood Nerissa K NK Kitcher Siân R SR Goodyear Richard J RJ Derudas Marco M Cantillon Daire M DM Baxendale Sarah S de la Vega de León Antonio A Mahieu Virginia N VN Osgood Richard T RT Wilson Charlotte Donald CD Bull James C JC Waddell Simon J SJ Whitfield Tanya T TT Ward Simon E SE Kros Corné J CJ Richardson Guy P GP

JCI insight 20210408 7

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 an ...[more]

PMID: 33735112

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Project description:BackgroundIrreversible hearing loss is a well-known adverse effect of aminoglycosides, however, inability to accurately predict ototoxicity is a major limitation in clinical care. We addressed this limitation by developing a prediction model for aminoglycoside ototoxicity applicable to the general population.MethodsWe employed a prospective non-drug-resistant tuberculosis (TB), non-HIV/AIDS cohort of 153 adults on Streptomycin based anti-TB therapy. High frequency pure-tone audiometry was done at regular intervals throughout the study. Clinical and audiological predictors of ototoxicity were collated and ototoxic threshold shift from the baseline audiogram computed. The prediction model was developed with logistic regression method by examining multiple predictors of ototoxicity. Series of models were fitted sequentially; the best model was identified using Akaike Information Criterion and likelihood ratio test. Key variables in the final model were used to develop a logit model for ototoxicity prediction.ResultsOtotoxicity occurred in 35% of participants. Age, gender, weight, cumulative Streptomycin dosage, social class, baseline pure tone average (PTA) and prior hearing symptoms were explored as predictors. Multiple logistic regression showed that models with age, cumulative dosage and baseline PTA were best for predicting ototoxicity. Regression parameters for ototoxicity prediction showed that yearly age increment raised ototoxicity risk by 5% (AOR = 1.05; CI, 1.01-1.09), and a gram increase in cumulative dosage increased ototoxicity risk by 7% (AOR = 1.05; CI, 1.05-1.12) while a unit change in baseline log (PTA) was associated 254% higher risk of ototoxicity (AOR = 3.54, CI: 1.25, 10.01). Training and validation models had area under the receiver operating characteristic curve as 0.84 (CI, 0.76-0.92) and 0.79 (CI, 0.62-0.96) respectively, showing the model has discriminatory ability.ConclusionThis model can predict aminoglycoside ototoxicity in the general population.

Dataset Information

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

Publications

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

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