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The antibacterial and NMDA receptor activating properties of aminoglycosides are dissociable

S C Harvey1, X Li, P Skolnick

  • 1Lilly Research Laboratories, Neuroscience Discovery, Eli Lilly and Company Corporate Center, Bldg. 48, Drop Code 0510, Indianapolis, IN, USA. harvey_scott_c@lilly.com

European Journal of Pharmacology
|January 14, 2000
PubMed

Insights

Aminoglycoside antibiotics can cause hearing and balance toxicity due to NMDA receptor activation. This study found that ototoxicity is not linked to antibacterial activity, suggesting safer antibiotic development is possible.

Area of Science:

  • Pharmacology
  • Neuroscience
  • Toxicology

Background:

  • Aminoglycoside antibiotics are crucial but limited by ototoxicity (vestibular and cochlear toxicity).
  • This toxicity may stem from excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors.
  • Evidence suggests a polyamine-like activation of NMDA receptors by aminoglycosides.

Purpose of the Study:

  • To investigate if the NMDA receptor modulatory effects of aminoglycosides are separable from their antibacterial properties.
  • To determine if structural modifications can dissociate ototoxicity from antibacterial efficacy.

Main Methods:

  • Evaluated apramycin derivatives for their ability to enhance [3H]dizocilpine binding to rat brain membranes.
  • Assessed the augmentation of agonist responses on recombinant (NR1A/2B) NMDA receptors in Xenopus oocytes.
  • Determined antibacterial potencies against Staphylococcus aureus and Escherichia coli.

Main Results:

  • No correlation was found between NMDA receptor modulation and minimum inhibitory antibacterial concentrations for the tested aminoglycoside derivatives.
  • The capacity to positively modulate NMDA receptors was independent of antibacterial potency against Gram-positive and Gram-negative bacteria.

Conclusions:

  • The positive modulatory effects of aminoglycosides on NMDA receptors are dissociable from their antibacterial activity.
  • These findings suggest the potential to develop novel aminoglycoside antibiotics with reduced ototoxicity.
  • Future research can focus on designing aminoglycosides that retain antibacterial efficacy while minimizing NMDA receptor-mediated side effects.

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