Aminoglycoside (AGA) antibiotics are potent and highly effective against a wide range of bacterial infections. However, deleterious side effects of moderate to severe ototoxicity and nephrotoxicity greatly limit their use to the treatment of life-threatening bacterial infections. AGAs activate cell death pathways leading to destruction of inner ear mechanosensory neuronal cells specialized for detecting and transducing sound vibrations. To address the need for a preventive medication for this irreversible drug-induced hearing loss, we previously screened 11,000 compound library-using zebrafish as the model system. Our most promising hit Proto-1, showed 50% hair cell protection (HC50) of 3-6 �M. Structure�activity relationship studies led to the identification of candidates with improved safety profiles and potencies (ca.10 to 100 fold). Employing a Proto-1-based affinity pull-down probe, further studies are underway to identify and validate the cellular target of Proto-1 analogs that orchestrate auditory neuronal cell survival against aminoglycoside-induced ototoxicity.

Towards chemoprevention of Aminoglycoside-induced hearing loss

248th National Meeting (2014)

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