Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin.
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.
Institut für Medizinische Mikrobiologie,  Universität Zürich, 8006 Zürich,  Switzerland.
Tanja
T
Matt
Chyan Leong
CL
Ng
Kathrin
K
Lang
Su-Hua
SH
Sha
Rashid
R
Akbergenov
Dmitri
D
Shcherbakov
Martin
M
Meyer
Stefan
S
Duscha
Jing
J
Xie
Srinivas R
SR
Dubbaka
Déborah
D
Perez-Fernandez
Andrea
A
Vasella
V
V
Ramakrishnan
Jochen
J
Schacht
Erik C
EC
Böttger
D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy*; D001665:Binding Sites / Q000187:drug effects; D003638:Deafness / Q000139:chemically induced* / Q000503:physiopathology; D015195:Drug Design; D005839:Gentamicins / Q000633:toxicity; D006168:Guinea Pigs; D057809:HEK293 Cells; D006198:Hair Cells, Auditory / Q000187:drug effects; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016296:Mutagenesis / Q000502:physiology; D009161:Mycobacterium / Q000187:drug effects; D009328:Nebramycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D009924:Organ Culture Techniques; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011817:Rabbits; D012156:Reticulocytes / Q000166:cytology; D012270:Ribosomes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D009328:Nebramycin; C011666:apramycin