Discovering new aminoglycosides to alleviate inner ear toxicity
Royal National Institute for Deaf People
Stanford University
Aminoglycosides are a class of widely used, broad spectrum antibiotics that cause hearing impairments in upwards of 20% of treated patients and even higher percentages if repeated treatments are needed or susceptible genetic mutations are present. Although aminoglycoside ototoxicity is a well-documented side-effect, there is still no FDA-approved treatment to prevent it.   Despite the availability of newer, less ototoxic and nephrotoxic antibiotics, aminoglycosides are still among the most commonly prescribed class of antibiotics worldwide because of their efficacy, low costs, and low rates of antibiotic resistance. Indeed, aminoglycosides are designated as one of the critically important antimicrobials for human medicine. In the US, it is the first line of treatment for neonatal and peripartum sepsis and complicated urinary tract infection. In cystic fibrosis patients who are prone to recurrent sinopulmonary infection as most patients now survive into adulthood, repeated treatment with aminoglycosides is common with resulting hearing loss at rates up to 47%. There is clearly a pressing need to reduce aminoglycoside ototoxicity.   Aminoglycosides cause permanent hearing loss resulting from the irreversible loss of cochlear hair cells. We have made significant progress in designing aminoglycosides with differential effects on the prokaryotic and eukaryotic ribosome to reduce ototoxicity while preserving antimicrobial activity in vitro and in vivo, devised novel chemical synthetic pathways, identified target sites on the aminoglycoside backbones to modify, and generated several lead compounds. The current proposal aims to: 1)_x0001_test and optimize lead compounds in in vivo ototoxicity and infection models 2)_x0001_test additional novel aminoglycoside analogues in vitro for ototoxicity and antimicrobial activities and ability to permeate hair cells.
5.1 Pharmaceuticals