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.
Highlights
Aminoglycoside antibiotics offer an effective treatment against life-threatening infections, including sepsis and tuberculosis [1, 2]
This approach yielded 477 compounds (Figure 1B), which were retested at 50 μM for their ability to protect the zebrafish hair cells from death caused by exposure to 10 μM gentamicin (Figure 1C). From these 2 screens, 64 compounds were identified (Figure 1C) that protected zebrafish lateral-line hair cells against both neomycin and gentamicin. These 64 compounds were tested at 50 μM for their ability to protect outer hair cells (OHCs) in mouse cochlear cultures from exposure to 5 μM gentamicin
20 compounds were identified that protected mouse cochlear OHCs against gentamicin-induced cell death (Figure 1D), 8 of which protected hair cells without causing overt signs of hair-bundle damage (Figure 1E)
Summary
Aminoglycoside antibiotics offer an effective treatment against life-threatening infections, including sepsis and tuberculosis [1, 2]. They do, cause dose-related nephro- and ototoxicity [3, 4]. Whereas damage to the kidneys is reversible [5], some degree of permanent hearing loss has been reported in approximately 20% of patients treated with aminoglycosides [6, 7]. The clinical use of these antibiotics will continue until further drugs are developed that are affordably priced, available worldwide, and effective against infections currently treated with aminoglycosides. Finding methods to prevent the associated hearing loss is critical
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