4′-O-substitutions determine selectivity of aminoglycoside antibiotics

Déborah Perez-Fernandez, Dmitri Shcherbakov, Tanja Matt, Chyan Leong Ng, Iwona Kudyba, Stefan Duscha, Heithem Boukari, Rashmi Patak, Srinivas Reddy Dubbaka, Kathrin Lang, Martin Meyer, Rashid Akbergenov, Pietro Freihofer, Swapna Vaddi, Pia Thommes, V. Ramakrishnan, Andrea Vasella, Erik C. Böttger

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4′,6′-O-acetal and 4′-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4′-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.

Original languageEnglish
Article number3112
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 28 Jan 2014

Fingerprint

ribosomes
antibiotics
Aminoglycosides
Ribosomes
Substitution reactions
selectivity
substitutes
Anti-Bacterial Agents
drugs
Pharmaceutical Preparations
Acetals
Chemical modification
acetals
Ether
mutations
Point Mutation
Human Activities
Binding Sites
ethers
rings

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Perez-Fernandez, D., Shcherbakov, D., Matt, T., Ng, C. L., Kudyba, I., Duscha, S., ... Böttger, E. C. (2014). 4′-O-substitutions determine selectivity of aminoglycoside antibiotics. Nature Communications, 5, [3112]. https://doi.org/10.1038/ncomms4112

4′-O-substitutions determine selectivity of aminoglycoside antibiotics. / Perez-Fernandez, Déborah; Shcherbakov, Dmitri; Matt, Tanja; Ng, Chyan Leong; Kudyba, Iwona; Duscha, Stefan; Boukari, Heithem; Patak, Rashmi; Dubbaka, Srinivas Reddy; Lang, Kathrin; Meyer, Martin; Akbergenov, Rashid; Freihofer, Pietro; Vaddi, Swapna; Thommes, Pia; Ramakrishnan, V.; Vasella, Andrea; Böttger, Erik C.

In: Nature Communications, Vol. 5, 3112, 28.01.2014.

Research output: Contribution to journalArticle

Perez-Fernandez, D, Shcherbakov, D, Matt, T, Ng, CL, Kudyba, I, Duscha, S, Boukari, H, Patak, R, Dubbaka, SR, Lang, K, Meyer, M, Akbergenov, R, Freihofer, P, Vaddi, S, Thommes, P, Ramakrishnan, V, Vasella, A & Böttger, EC 2014, '4′-O-substitutions determine selectivity of aminoglycoside antibiotics', Nature Communications, vol. 5, 3112. https://doi.org/10.1038/ncomms4112
Perez-Fernandez D, Shcherbakov D, Matt T, Ng CL, Kudyba I, Duscha S et al. 4′-O-substitutions determine selectivity of aminoglycoside antibiotics. Nature Communications. 2014 Jan 28;5. 3112. https://doi.org/10.1038/ncomms4112
Perez-Fernandez, Déborah ; Shcherbakov, Dmitri ; Matt, Tanja ; Ng, Chyan Leong ; Kudyba, Iwona ; Duscha, Stefan ; Boukari, Heithem ; Patak, Rashmi ; Dubbaka, Srinivas Reddy ; Lang, Kathrin ; Meyer, Martin ; Akbergenov, Rashid ; Freihofer, Pietro ; Vaddi, Swapna ; Thommes, Pia ; Ramakrishnan, V. ; Vasella, Andrea ; Böttger, Erik C. / 4′-O-substitutions determine selectivity of aminoglycoside antibiotics. In: Nature Communications. 2014 ; Vol. 5.
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