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.

Abstract

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.

• Authors: Amr Sonousi, Vikram A Sarpe, Margarita Brilkova, Jochen Schacht, Andrea Vasella, Erik C Böttger, David Crich
• Journal: ACS infectious diseases (ACS Infect Dis) Vol. 4 Issue 7 Pg. 1114-1120 (07 13 2018) ISSN: 2373-8227 [Electronic] United States
• PMID: 29708331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aminoglycosides
• Anti-Bacterial Agents
• Sisomicin

Topics

• Aminoglycosides (chemical synthesis, chemistry, pharmacology)
• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
• Base Sequence
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Escherichia coli (drug effects)
• Humans
• Microbial Sensitivity Tests
• Protein Biosynthesis (drug effects)
• Ribosomes (physiology)
• Sisomicin (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship