Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin

T Matt, CL Ng, K Lang, SH Sha… - Proceedings of the …, 2012 - National Acad Sciences
T Matt, CL Ng, K Lang, SH Sha, R Akbergenov, D Shcherbakov, M Meyer, S Duscha, J Xie…
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
Aminoglycosides are potent antibacterials, but therapy is compromised by substantial
toxicity causing, in particular, irreversible hearing loss. Aminoglycoside ototoxicity occurs
both in a sporadic dose-dependent and in a genetically predisposed fashion. We recently
have developed a mechanistic concept that postulates a key role for the mitochondrial
ribosome (mitoribosome) in aminoglycoside ototoxicity. We now report on the surprising
finding that apramycin, a structurally unique aminoglycoside licensed for veterinary use …
Aminoglycosides are potent antibacterials, but therapy is compromised by substantial toxicity causing, in particular, irreversible hearing loss. Aminoglycoside ototoxicity occurs both in a sporadic dose-dependent and in a genetically predisposed fashion. We recently have developed a mechanistic concept that postulates a key role for the mitochondrial ribosome (mitoribosome) in aminoglycoside ototoxicity. We now report on the surprising finding that apramycin, a structurally unique aminoglycoside licensed for veterinary use, shows little activity toward eukaryotic ribosomes, including hybrid ribosomes which were genetically engineered to carry the mitoribosomal aminoglycoside-susceptibility A1555G allele. In ex vivo cultures of cochlear explants and in the in vivo guinea pig model of chronic ototoxicity, apramycin causes only little hair cell damage and hearing loss but it is a potent antibacterial with good activity against a range of clinical pathogens, including multidrug-resistant Mycobacterium tuberculosis. These data provide proof of concept that antibacterial activity can be dissected from aminoglycoside ototoxicity. Together with 3D structures of apramycin-ribosome complexes at 3.5-Å resolution, our results provide a conceptual framework for further development of less toxic aminoglycosides by hypothesis-driven chemical synthesis.
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