1. Eur J Med Chem. 2018 Sep 5;157:1512-1525. doi: 10.1016/j.ejmech.2018.08.022. Epub
2018 Aug 11.

Broad-spectrum antibacterial amphiphilic aminoglycosides: A new focus on the
structure of the lipophilic groups extends the series of active dialkyl neamines.

Zimmermann L(1), Kempf J(1), Briée F(1), Swain J(2), Mingeot-Leclercq MP(2),
Décout JL(3).

Author information: 
(1)Univ. Grenoble Alpes, CNRS, Département de Pharmacochimie Moléculaire, 38000, 
Grenoble, France.
(2)Université catholique de Louvain, Louvain Drug Research Institute, Unité de
Pharmacologie Cellulaire et Moléculaire, Avenue E. Mounier 73, B1.73.05, B-1200, 
Brussels, Belgium.
(3)Univ. Grenoble Alpes, CNRS, Département de Pharmacochimie Moléculaire, 38000, 
Grenoble, France. Electronic address: Jean-Luc.Decout@univ-grenoble-alpes.fr.

Amphiphilic aminoglycosides (AAGs) constitute a new class of antibacterial
compounds targeting the bacterial membranes. We have identified the 3',6-dinonyl 
neamine 9 as a broad spectrum antibacterial AAG. Here, we report on the
synthesis, antibacterial activity and eukaryotic cytotoxicity of new 3',6-dialkyl
neamines designed in order to finely delineate the structure-activity
relationships relating their activity to a lipophilicity window. New
broad-spectrum antibacterial derivatives were obtained carrying two identical
linear or branched alkyl groups or two different linear alkyl groups. Two
fluorescent antibacterial 3',6-heterodialkyl neamines carrying a pyrenylbutyl
fluorophore were also identified as potential tools for mechanistic study.
Homodialkyl and heterodialkyl neamines appeared to be more active on
Gram-negative bacteria than dinaphthylalkyl neamines. However, branched dialkyl
neamines or heterodialkyl derivatives were found to be more cytotoxic on
mammalian cells than 9. The exposure of P. aeruginosa over one month to half-MIC 
of one of the most active derivatives 9 demonstrated the high difficulty of
resistance emergence to AAGs.

Copyright © 2018 Elsevier Masson SAS. All rights reserved.

DOI: 10.1016/j.ejmech.2018.08.022 
PMID: 30282323  [Indexed for MEDLINE]