1. Antimicrob Agents Chemother. 2014 Aug;58(8):4420-30. doi: 10.1128/AAC.02536-13.
Epub 2014 May 27.

New Amphiphilic Neamine Derivatives Active against Resistant Pseudomonas
aeruginosa and Their Interactions with Lipopolysaccharides.

Sautrey G(1), Zimmermann L(2), Deleu M(3), Delbar A(1), Souza Machado L(2),
Jeannot K(4), Van Bambeke F(1), Buyck JM(1), Decout JL(2), Mingeot-Leclercq

Author information: 
(1)Université Catholique de Louvain, Louvain Drug Research Institute, Pharmacologie 
Cellulaire et Moléculaire, Brussels, Belgium.
(2)Université Grenoble Alpes, Joseph Fourier/CNRS, UMR 5063, Département de
Pharmacochimie Moléculaire, ICMG FR 2607, Grenoble, France.
(3)Université de Liège, Gembloux Agro-Bio Tech, Laboratoire de Biophysique
Moléculaire aux Interfaces, Gembloux, Belgium.
(4)Centre National de Référence de la Résistance aux Antibiotiques, Laboratoire de
Bactériologie, Centre Hospitalier Régional Universitaire Jean Minjoz, Besançon,
(5)Université Catholique de Louvain, Louvain Drug Research Institute, Pharmacologie 
Cellulaire et Moléculaire, Brussels, Belgium marie-paule.mingeot@uclouvain.be.

The development of novel antimicrobial agents is urgently required to curb the
widespread emergence of multidrug-resistant bacteria like colistin-resistant
Pseudomonas aeruginosa. We previously synthesized a series of amphiphilic neamine
derivatives active against bacterial membranes, among which
3',6-di-O-[(2″-naphthyl)propyl]neamine (3',6-di2NP),
3',6-di-O-[(2″-naphthyl)butyl]neamine (3',6-di2NB), and 3',6-di-O-nonylneamine
(3',6-diNn) showed high levels of activity and low levels of cytotoxicity (L.
Zimmermann et al., J. Med. Chem. 56:7691-7705, 2013). We have now further
characterized the activity of these derivatives against colistin-resistant P.
aeruginosa and studied their mode of action; specifically, we characterized their
ability to interact with lipopolysaccharide (LPS) and to alter the bacterial
outer membrane (OM). The three amphiphilic neamine derivatives were active
against clinical colistin-resistant strains (MICs, about 2 to 8 μg/ml), The most 
active one (3',6-diNn) was bactericidal at its MIC and inhibited biofilm
formation at 2-fold its MIC. They cooperatively bound to LPSs, increasing the
outer membrane permeability. Grafting long and linear alkyl chains (nonyl)
optimized binding to LPS and outer membrane permeabilization. The effects of
amphiphilic neamine derivatives on LPS micelles suggest changes in the
cross-bridging of lipopolysaccharides and disordering in the hydrophobic core of 
the micelles. The molecular shape of the 3',6-dialkyl neamine derivatives induced
by the nature of the grafted hydrophobic moieties (naphthylalkyl instead of
alkyl) and the flexibility of the hydrophobic moiety are critical for their
fluidifying effect and their ability to displace cations bridging LPS. Results
from this work could be exploited for the development of new amphiphilic neamine 
derivatives active against colistin-resistant P. aeruginosa.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

PMID: 24867965  [PubMed - in process]