title: New amphiphilic neamine derivatives active against resistant Pseudomonas aeruginosa and their interactions with lipopolysaccharides.
abstract: 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.
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire, Brussels, Belgium.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sautrey
authors.affiliation: Université Grenoble Alpes, Joseph Fourier/CNRS, UMR 5063, Département de Pharmacochimie Moléculaire, ICMG FR 2607, Grenoble, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Zimmermann
authors.affiliation: Université de Liège, Gembloux Agro-Bio Tech, Laboratoire de Biophysique Moléculaire aux Interfaces, Gembloux, Belgium.
authors.forename: Magali
authors.initials: M
authors.lastname: Deleu
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire, Brussels, Belgium.
authors.forename: Alicia
authors.initials: A
authors.lastname: Delbar
authors.affiliation: Université Grenoble Alpes, Joseph Fourier/CNRS, UMR 5063, Département de Pharmacochimie Moléculaire, ICMG FR 2607, Grenoble, France.
authors.forename: Luiza
authors.initials: L
authors.lastname: Souza Machado
authors.affiliation: Centre National de Référence de la Résistance aux Antibiotiques, Laboratoire de Bactériologie, Centre Hospitalier Régional Universitaire Jean Minjoz, Besançon, France.
authors.forename: Katy
authors.initials: K
authors.lastname: Jeannot
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire, Brussels, Belgium.
authors.forename: Julien M
authors.initials: JM
authors.lastname: Buyck
authors.affiliation: Université Grenoble Alpes, Joseph Fourier/CNRS, UMR 5063, Département de Pharmacochimie Moléculaire, ICMG FR 2607, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Decout
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire, Brussels, Belgium marie-paule.mingeot@uclouvain.be.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D003091:Colistin / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D005601:Framycetin / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008070:Lipopolysaccharides / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D009281:Naphthalenes; D005601:Framycetin; C488396:neamine; D003091:Colistin