New Broad-Spectrum Antibacterial Amphiphilic Aminoglycosides Active against Resistant Bacteria: From Neamine Derivatives to Smaller Neosamine Analogues

Aminoglycosides
(AGs) constitute a major family of potent and broad-spectrum
antibiotics disturbing protein synthesis through binding to the A
site of 16S rRNA. Decades of widespread clinical use of AGs strongly
reduced their clinical efficacy through the selection of resistant
bacteria. Recently, conjugation of lipophilic groups to AGs generated
a novel class of potent antibacterial amphiphilic aminoglycosides
(AAGs) with significant improved activities against various sensitive
and resistant bacterial strains. We have identified amphiphilic 3′,6-dialkyl
derivatives of the small aminoglycoside neamine as broad spectrum
antibacterial agents targeting bacterial membranes. Here, we report
on the synthesis and the activity against sensitive and resistant
Gram-negative and/or Gram-positive bacteria of new amphiphilic 3′,4′-dialkyl
neamine derivatives and of their smaller analogues in the 6-aminoglucosamine
(neosamine) series prepared from N-acetylglucosamine.