IDENTIFICATION AND TRANSLATION OF COMPOUNDS THAT PROTECT AGAINST AMINOGLYCOSIDE-INDUCED HEARING LOSS

Alexandria Hudson

Hearing loss is the third most common physical health problem in the U.S and can result from damage to sensory hair cells that normally function to transduce mechanical stimulation into electrical stimuli perceived by the brain. In mammals, damaged hair cells are not replaced. This inability to regenerate hair cells can be devastating since hearing loss is permanent and can lead to social isolation and decreased employment. Hair cells are prone to damage resulting from aging, noise exposure and medications such as aminoglycoside antibiotics. Aminoglycoside antibiotics are some of the most efficacious drugs to treat life threatening gram-negative bacterial infections and their success is largely attributed to their rapid concentration-dependent bactericidal effects and low incidence of resistance, surpassing expensive antibiotics with fewer harmful side effects. Aminoglycoside-induced hearing loss is found in 20–30% of patients undergoing therapy. Despite numerous studies identifying promising compounds to protect against aminoglycoside ototoxicity there are currently no FDA-approved treatments. A number of challenges including multiple mechanisms of damage for different aminoglycosides, an incomplete understanding of the cochlear immune system, and challenges in translating drug success in preclinical models have emerged as roadblocks to making therapeutic advances. My dissertation builds on previous work in zebrafish, investigating analogs of berbamine, an anti-inflammatory compound, to determine the extent of their protection against aminoglycoside-induced hearing loss and their interaction with the immune system to determine their protective mechanism. Zebrafish hair cells are structurally and functionally similar to mammalian hair cells and show similar responses to ototoxic damage, making these fish a popular model in hearing research. My dissertation also continues former zebrafish work by translating MM201 (a hepatocyte growth factor mimetic) into rodents for developing a hearing therapy. This dissertation contributes to the understanding of aminoglycoside-induced hearing loss pathology by identifying structures that enhance protection from aminoglycoside-induced hearing loss. I also show the extent to which berbamine analogs modulate the macrophage response to aminoglycosides and offer recommendations for translating zebrafish hearing loss protectants into rodents. Overall, I have promising lead compounds for further development to meet the therapeutic goal of devising a protective hearing loss drug candidate.

IDENTIFICATION AND TRANSLATION OF COMPOUNDS THAT PROTECT AGAINST AMINOGLYCOSIDE-INDUCED HEARING LOSS

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