The antibacterial and NMDA receptor activating properties of aminoglycosides are dissociable

The use of aminoglycoside antibiotics is limited by side effects, the most critical of which are vestibular and cochlear toxicity. Recent evidence ind icates that these effects result from an excitotoxic process mediated, at l east in part, through a polyamine-like activation of NMDA receptors. This s tudy investigated whether these positive modulatory effects of aminoglycosi des at NMDA receptors are dissociable from their antibacterial properties. A group of structurally related apramycin derivatives was evaluated for the ability to enhance [H-3]dizocilpine binding to rat brain membranes, and fo r the ability to augment agonist responses on recombinant (NR1A/2B) NMDA re ceptors expressed in Xenopus oocytes. Based on the antibacterial potencies of these derivatives against Staphylococcus aureus and Escherichia coli, it is concluded that there is no correlation between the ability of an aminog lycoside to produce a positive modulation of NMDA receptors and minimum inh ibitory antibacterial concentrations. These findings indicate that it may b e possible to develop an aminoglycoside antibiotic with reduced potential f or ototoxicity. (C) 2000 Elsevier Science B.V. All rights reserved.