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ACS Infect Dis. 2018 Jul 13;4(7):1114-1120. doi: 10.1021/acsinfecdis.8b00052. Epub 2018 May 10.

Effects of the 1- N-(4-Amino-2 S-hydroxybutyryl) and 6'- N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics.

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Department of Chemistry , Wayne State University , 5101 Cass Avenue , Detroit , Michigan 48202 , United States.
Institut für Medizinische Mikrobiologie , Universität Zürich , Gloriastrasse 28/30 , 8006 Zürich , Switzerland.
Kresge Hearing Research Institute, Department of Otolaryngology , University of Michigan , 1150 West Medical Center Drive , Ann Arbor , Michigan 48109 , United States.
Laboratorium für Organische Chemie , ETH Zürich , Vladimir-Prelog-Weg 1-5/10 , 8093 Zürich , Switzerland.


Syntheses of the 6'- N-(2-hydroxyethyl) and 1- N-(4-amino-2 S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1- N-(4-amino-2 S-hydroxybutyryl)-6'- N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'- N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1- N-(4-amino-2 S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6'- N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6') aminoglycoside-modifying enzymes, while the 1- N-(4-amino-2 S-hydroxybutyryl) modification overcomes resistance to the AAC(2') class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates.


aminoglycoside-modifying enzymes; aminoglycosides; cell-free translation assays; ribosomal methyltransferases; structure−activity relationship

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