4'-O-substitutions determine selectivity of aminoglycoside antibiotics.
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.
1] Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland [2].
Déborah
D
Perez-Fernandez
1] Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland [2].
Dmitri
D
Shcherbakov
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Tanja
T
Matt
1] MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK [2] Institute of Systems Biology, Universiti Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia [3].
Ng Chyan
NC
Leong
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
Iwona
I
Kudyba
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Stefan
S
Duscha
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Heithem
H
Boukari
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
Rashmi
R
Patak
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
Srinivas Reddy
SR
Dubbaka
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
Kathrin
K
Lang
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Martin
M
Meyer
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Rashid
R
Akbergenov
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Pietro
P
Freihofer
Euprotec Limited, Unit 12 Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
Swapna
S
Vaddi
Euprotec Limited, Unit 12 Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK.
Pia
P
Thommes
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
V
V
Ramakrishnan
Laboratorium für Organische Chemie, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
Andrea
A
Vasella
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Erik C
EC
Böttger
D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D002474:Cell-Free System; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004347:Drug Interactions; D004926:Escherichia coli / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis / Q000187:drug effects; D012336:RNA, Ribosomal, 16S / Q000737:chemistry / Q000235:genetics; D012270:Ribosomes / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D012336:RNA, Ribosomal, 16S