4′-O-substitutions determine selectivity of aminoglycoside antibiotics

Déborah Perez-Fernandez, Dmitri Shcherbakov, Tanja Matt, Ng Chyan Leong, 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 () and Erik C. Böttger ()
Additional contact information
Déborah Perez-Fernandez: Laboratorium für Organische Chemie, ETH Zürich
Dmitri Shcherbakov: Institut für Medizinische Mikrobiologie, Universität Zürich
Tanja Matt: Institut für Medizinische Mikrobiologie, Universität Zürich
Ng Chyan Leong: MRC Laboratory of Molecular Biology
Iwona Kudyba: Laboratorium für Organische Chemie, ETH Zürich
Stefan Duscha: Institut für Medizinische Mikrobiologie, Universität Zürich
Heithem Boukari: Institut für Medizinische Mikrobiologie, Universität Zürich
Rashmi Patak: Laboratorium für Organische Chemie, ETH Zürich
Srinivas Reddy Dubbaka: Laboratorium für Organische Chemie, ETH Zürich
Kathrin Lang: MRC Laboratory of Molecular Biology
Martin Meyer: Institut für Medizinische Mikrobiologie, Universität Zürich
Rashid Akbergenov: Institut für Medizinische Mikrobiologie, Universität Zürich
Pietro Freihofer: Institut für Medizinische Mikrobiologie, Universität Zürich
Swapna Vaddi: Euprotec Limited, Unit 12 Williams House, Manchester Science Park
Pia Thommes: Euprotec Limited, Unit 12 Williams House, Manchester Science Park
V. Ramakrishnan: MRC Laboratory of Molecular Biology
Andrea Vasella: Laboratorium für Organische Chemie, ETH Zürich
Erik C. Böttger: Institut für Medizinische Mikrobiologie, Universität Zürich

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4112

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