Ototoxicity is thought to be inherent to aminoglycosides, compromising the clinical use of these important antibacterials. While we have shown clinically successful pharmacological mitigation of aminoglycoside-induced hearing loss (New Engl. J. Med. 354:1856-1857, 2006), chemotherapy of the future would benefit from aminoglycosides effective against multi-drug resistant bacteria but with no or little ototoxic potential.

We have entered collaborations with the laboratories of Dr. Erik Böttger (Zürich) and Dr. Timor Baasov (Haifa) in order to develop non-ototoxic designer aminoglycosides as antibacterials and as stop-codon suppressors. Potential ototoxicity is determined during the design phase of new drugs by a screen with explants from the inner ear of CBA mice and in guinea pigs in vivo. Our mechanistic concept postulates a key role for the mitochondrial ribosome in aminoglycoside ototoxicity (Hear. Res. 303:12-19, 2013). We have earlier reported (PNAS 109:10984-10989, 2012) that apramycin, a structurally unique aminoglycoside in veterinary oral use for treatment of intestinal infections, shows low activity towards eukaryotic ribosomes, including hybrid ribosomes carrying the aminoglycoside-susceptibility A1555G allele. This finding led to the proof-of-concept that antibacterial activity can be dissected from aminoglycoside ototoxicity, and we have now developed aminoglycoside compounds with low ototoxic potential. New lead compounds promise a safety margin (antibacterial efficacy vs. ototoxicity) more than an order of magnitude better than gentamicin.