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 indicates that these effects result from an excitotoxic process mediated, at least in part, through a polyamine-like activation of NMDA receptors. This study investigated whether these positive modulatory effects of aminoglycosides at NMDA receptors are dissociable from their antibacterial properties. A group of structurally related apramycin derivatives was evaluated for the ability to enhance [3H]dizocilpine binding to rat brain membranes, and for the ability to augment agonist responses on recombinant (NR1A/2B) NMDA receptors 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 aminoglycoside to produce a positive modulation of NMDA receptors and minimum inhibitory antibacterial concentrations. These findings indicate that it may be possible to develop an aminoglycoside antibiotic with reduced potential for ototoxicity.
Harvey
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SC
Lilly Research Laboratories, Neuroscience Discovery, Eli Lilly and Company Corporate Center, Bldg. 48, Drop Code 0510, Indianapolis, IN, USA. harvey_scott_c@lilly.com
Li
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Skolnick
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P
Kirst
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HA
D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009328:Nebramycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects; D014316:Tritium; D014981:Xenopus
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D018075:RNA, Complementary; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D009328:Nebramycin; C011666:apramycin; D016291:Dizocilpine Maleate