Potential therapeutic targets to prevent hearing loss caused by antibiotics identified by researchers

Researchers at Indiana University School of Medicine are developing new methods to investigate whether an antibiotic causes hair cell death and irreversible hearing loss in humans.

In a paper published recently in Developmental Cell, the researchers described how they discovered an autophagy pathway in hair cells that is connected to persistent hearing loss caused by aminoglycosides, a kind of antibiotic. In addition, the researchers created one of the first laboratory models resistant to aminoglycoside-induced hearing loss.

“This work identifies multiple potential therapeutic targets for preventing hearing loss caused by aminoglycosides,” said Bo Zhao, PhD, assistant professor of otolaryngology–head and neck surgery.

Ototoxicity–hearing loss caused by medication–is one of the humans’ main causes of hearing loss. More than 48 million people in the United States experience trouble hearing.

Aminoglycosides for nearly a century have been used to treat severe infections. Although the drug is a first-line treatment for life-threatening infections–particularly in developing countries–due to its low cost and low incidence of antibiotic resistance, it has been reported to cause hair cell death and subsequent permanent hearing loss among 20-47 per cent of patients, but the underlying mechanisms are not clear. Hair cells are responsible for sound reception in the inner ear.

Zhao, whose lab investigates the molecular mechanisms underlying hearing loss, used biochemical screening to identify proteins found in hair cells. They first discovered that aminoglycosides are bound to the protein RIPOR2, which is required for auditory perception.

“As aminoglycosides specifically trigger a rapid localization change of RIPOR2 in hair cells, we hypothesize that RIPOR2 is essential for aminoglycoside-induced hair cell death,” Zhao said.

The researchers developed a model in the lab that has normal hearing but significantly decreased RIPOR2 expression. Through these experiments, Zhao said the model had neither significant hair cell death nor hearing loss after treatment of aminoglycosides.

“We then discovered RIPOR2 regulates the autophagy pathway in hair cells. Knowing this, we developed other laboratory models without the expression of several key autophagy proteins that did not exhibit hair cell death or hearing loss when treated with the antibiotic,” said Jinan Li, PhD, a postdoctoral fellow in the Zhao lab and first author of the paper.

According to the research’s authors, the proteins discovered in this study might be exploited as therapeutic targets in future studies to prevent aminoglycoside-induced hearing loss.

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