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

Tanja Matt, Chyan Leong Ng, Kathrin Lang, Su Hua Sha, Rashid Akbergenov, Dmitri Shcherbakov, Martin Meyer, Stefan Duscha, Jing Xie, Srinivas R. Dubbaka, Déborah Perez-Fernandez, Andrea Vasella, V. Ramakrishnan, Jochen Schacht, Erik C. Böttger

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)10984-10989
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number27
DOIs
Publication statusPublished - 3 Jul 2012

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Aminoglycosides
Ribosomes
Hearing Loss
Multidrug-Resistant Tuberculosis
Poisons
Cochlea
2-deoxystreptamine
apramycin
Mycobacterium tuberculosis
Guinea Pigs
Alleles

Keywords

  • Antibiotic
  • Deafness
  • Misreading
  • Mycobacteria
  • Translation

ASJC Scopus subject areas

  • General

Cite this

Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin. / Matt, Tanja; Ng, Chyan Leong; Lang, Kathrin; Sha, Su Hua; Akbergenov, Rashid; Shcherbakov, Dmitri; Meyer, Martin; Duscha, Stefan; Xie, Jing; Dubbaka, Srinivas R.; Perez-Fernandez, Déborah; Vasella, Andrea; Ramakrishnan, V.; Schacht, Jochen; Böttger, Erik C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 27, 03.07.2012, p. 10984-10989.

Research output: Contribution to journalArticle

Matt, T, Ng, CL, Lang, K, Sha, SH, Akbergenov, R, Shcherbakov, D, Meyer, M, Duscha, S, Xie, J, Dubbaka, SR, Perez-Fernandez, D, Vasella, A, Ramakrishnan, V, Schacht, J & Böttger, EC 2012, 'Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 27, pp. 10984-10989. https://doi.org/10.1073/pnas.1204073109
Matt, Tanja ; Ng, Chyan Leong ; Lang, Kathrin ; Sha, Su Hua ; Akbergenov, Rashid ; Shcherbakov, Dmitri ; Meyer, Martin ; Duscha, Stefan ; Xie, Jing ; Dubbaka, Srinivas R. ; Perez-Fernandez, Déborah ; Vasella, Andrea ; Ramakrishnan, V. ; Schacht, Jochen ; Böttger, Erik C. / Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 27. pp. 10984-10989.
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