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.
Département de Pharmacochimie Moléculaire, ICMG FR 2607, University Grenoble Alpes/CNRS, UMR 5063 , 470 Rue de la Chimie, BP 53, F-38041 Grenoble, France.
Louis
L
Zimmermann
Département de Pharmacochimie Moléculaire, ICMG FR 2607, University Grenoble Alpes/CNRS, UMR 5063 , 470 Rue de la Chimie, BP 53, F-38041 Grenoble, France.
Indrajit
I
Das
Département de Pharmacochimie Moléculaire, ICMG FR 2607, University Grenoble Alpes/CNRS, UMR 5063 , 470 Rue de la Chimie, BP 53, F-38041 Grenoble, France.
Jérôme
J
Désiré
Unité de Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain , Avenue E. Mounier 73, B1.73.05, B-1200 Brussels, Belgium.
Guillaume
G
Sautrey
Département de Pharmacochimie Moléculaire, ICMG FR 2607, University Grenoble Alpes/CNRS, UMR 5063 , 470 Rue de la Chimie, BP 53, F-38041 Grenoble, France.
Vinicius
V
Barros R S
Unité de Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain , Avenue E. Mounier 73, B1.73.05, B-1200 Brussels, Belgium.
Micheline
M
El Khoury
Unité de Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain , Avenue E. Mounier 73, B1.73.05, B-1200 Brussels, Belgium.
Marie-Paule
MP
Mingeot-Leclercq
Département de Pharmacochimie Moléculaire, ICMG FR 2607, University Grenoble Alpes/CNRS, UMR 5063 , 470 Rue de la Chimie, BP 53, F-38041 Grenoble, France.
Jean-Luc
JL
Décout
D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005601:Framycetin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D013501:Surface-Active Agents; D005601:Framycetin; C488396:neamine; D005944:Glucosamine