Structures of several aminoglycoside antibiotics. Chirality is indicated by the Natta projection method.

Cell death mechanisms induced by aminoglycosides. (1) Aminoglycosides can enter cells by permeating cation channels directly into the cytosol. Binding of aminoglycosides to iron generates ROS, with arachidonic acid (AA) acting as an electron donor. ROS activates Bax, which in turn translocates to mitochondrial membranes. (2) Cytochrome c (cyt c) is released from mitochondria through the mitochondrial transition pore formed by Bax-dependent mechanisms, activating caspase-9 and caspase-3, and leading to apoptosis. ROS are also released from mitochondria, further increasing cytosolic ROS levels. (3) In caspase-independent mechanisms, EndoG and AIF released from mitochondria also induce apoptosis. (4) Aminoglycosides can also be endocytosed and are trafficked to the ER and lysosome by vesicle transport mechanisms. (5) Aminoglycosides can induce lysosomal rupture, or the release of lysosomal cathepsins, either of which leads to necrosis. (6) Aminoglycosides within the lumen of the ER bind to CLIMP-63, inducing oligomerization that can activate 14-3-3 proteins, leading to mitochondrial apoptosis signaling and/or resulting in JNK activation and c-Jun translocation into nucleus. (7) The c-Jun transcription factor induces apoptotic gene transcription and subsequent apoptosis.

Schematic diagram of the cochlear duct cytoarchitecture and its electrophysiological environments. The stria vascularis, lining the spiral ligament on the inside lateral wall of the bony cochlear shell, contains basal (B) and marginal (M) cells connected together by tight junctions that form an impermeable paracellular barrier to solutes. Circulating aminoglycosides within strial capillaries (C) are preferentially transported through the strial blood–labyrinth barrier consisting of tight junction-coupled endothelial cells, into the intra-strial space (ISS). From there, aminoglycosides are trafficked through marginal cells into endolymph, and enter hair cells (HC) across their apical surfaces by endocytosis and non-selective cation channel permeation. The electrical potentials of various fluid compartments, separated by tight junction-coupled endothelial and epithelial cell barrier layers, are also indicated. Endolymph has a +80 mV, and hair cells have a resting potential of −60 to −75 mV, generating a considerable electrophoretic driving force across the apical endolymphatic membranes of hair cells.