LAUSR

Although aminoglycoside antibiotics are effective against Gram-negative infections, these drugs often cause irreversible hearing damage. Binding to the decoding site of eukaryotic ribosomes appears to result in ototoxicity, but there is evidence that other effects are involved. Here we show how chemical modifications of apramycin and geneticin, considered amongst the least and most toxic aminoglycosides, respectively, reduce auditory cell damage. Using molecular dynamics simulations, we studied how modified aminoglycosides influence the essential freedom of movement of the decoding site of the ribosome, the region targeted by aminoglycosides. By determining the ratio of a protein translated in mitochondria to that of a protein translated in the cytoplasm, we showed that aminoglycosides can paradoxically elevate rather than reduce protein levels. We showed that certain aminoglycosides induce rapid plasma membrane permeabilization and that this non-ribosomal effect can also be reduced through chemical modifications. The results presented suggest a new paradigm for the development of safer aminoglycoside antibiotics.