Abstract
Aminoglycosides are potent antibiotics deployed worldwide despite their known side-effect of sensorineural hearing loss. The main etiology of this sensory deficit is death of inner ear sensory hair cells selectively triggered by aminoglycosides. For decades, research has sought to unravel the molecular events mediating sensory cell demise, emphasizing the roles of reactive oxygen species and their potentials as therapeutic targets. Studies in recent years have revealed candidate transport pathways including the mechanotransducer channel for drug entry into sensory cells. Once inside sensory cells, intracellular targets of aminoglycosides, such as the mitochondrial ribosomes, are beginning to be elucidated. Based on these results, less ototoxic aminoglycoside analogs are being generated and may serve as alternate antimicrobial agents. In this article, we review the latest findings on mechanisms of aminoglycoside entry into hair cells, their intracellular actions and potential therapeutic targets for preventing aminoglycoside ototoxicity.
Highlights
Aminoglycosides are critical antimicrobials with potent activities against gram negative bacteria (World Health Organization, 2011)
While this study shows that it is possible to separate aminoglycoside entry into hair cells from entry into bacteria, more work is needed to gain insights into the relationship between aminoglycoside structure and antimicrobial actions, in particular bacterial uptake
How are novel aminoglycosides less ototoxic? It remains incompletely understood how novel aminoglycosides that have been developed are less ototoxic (Matt et al, 2012; Perez-Fernandez et al, 2014; Huth et al, 2015). Will this shape the development of the generation of safer aminoglycoside antibiotics but it will be relevant to those using aminoglycosides for codon-read-through therapies for rare diseases (Baradaran-Heravi et al, 2017)
Summary
Aminoglycosides are critical antimicrobials with potent activities against gram negative bacteria (World Health Organization, 2011). In other studies, decreased GTTR uptake is observed using high calcium in the extracellular solution, which leads to a reduction in hair cell loss caused by aminoglycoside treatment in both the lateral line in vivo and cochlea in vitro (Coffin et al, 2009; Wang and Steyger, 2009; Ou et al, 2012). The strongest evidence supporting the role of the mitoribosome in aminoglycoside ototoxicity is antibiotic hypersensitivity in patients with the m.1555A>G mitochondrial DNA mutation (Hutchin et al, 1993; Prezant et al, 1993; Estivill et al, 1998) Patients with this mutation located adjacent to the aminoglycoside ribosomal binding site are susceptible to aminoglycoside induced hearing loss. In vitro experiments show the depletion of glutathione (a major ROS scavenger) does not increase susceptibility to aminoglycoside induced cell death suggesting alternate roles for ROS (Majumder et al, 2015)
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