The membrane-active polyaminoisoprenyl compound NV716 re-sensitizes Pseudomonas aeruginosa to antibiotics and reduces bacterial virulence.
Gang Wang, Jean-Michel Brunel, Matthias Preusse, Negar Mozaheb, Sven D Willger, Gerald Larrouy-Maumus, Pieter Baatsen, Susanne Häussler, Jean-Michel Bolla, Françoise Van Bambeke
Author Information
Gang Wang: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Jean-Michel Brunel: Aix Marseille Université, INSERM, SSA, Membranes et Cibles thérapeutiques (MCT), Marseille, France. ORCID
Matthias Preusse: Department of Molecular Bacteriology, Helmoltz Centre for Infection Research, Braunschweig, Germany. ORCID
Negar Mozaheb: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. ORCID
Sven D Willger: Department of Molecular Bacteriology, Helmoltz Centre for Infection Research, Braunschweig, Germany. ORCID
Gerald Larrouy-Maumus: Department of Life Sciences, Faculty of Natural Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
Pieter Baatsen: Electron Microscopy Platform & Bio Imaging Core, VIB & KULeuven Center for Brain & Disease Research, KULeuven, Leuven, Belgium.
Susanne Häussler: Department of Molecular Bacteriology, Helmoltz Centre for Infection Research, Braunschweig, Germany. ORCID
Jean-Michel Bolla: Aix Marseille Université, INSERM, SSA, Membranes et Cibles thérapeutiques (MCT), Marseille, France. ORCID
Françoise Van Bambeke: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. francoise.vanbambeke@uclouvain.be. ORCID
Pseudomonas aeruginosa is intrinsically resistant to many antibiotics due to the impermeability of its outer membrane and to the constitutive expression of efflux pumps. Here, we show that the polyaminoisoprenyl compound NV716 at sub-MIC concentrations re-sensitizes P. aeruginosa to abandoned antibiotics by binding to the lipopolysaccharides (LPS) of the outer membrane, permeabilizing this membrane and increasing antibiotic accumulation inside the bacteria. It also prevents selection of resistance to antibiotics and increases their activity against biofilms. No stable resistance could be selected to NV716-itself after serial passages with subinhibitory concentrations, but the transcriptome of the resulting daughter cells shows an upregulation of genes involved in the synthesis of lipid A and LPS, and a downregulation of quorum sensing-related genes. Accordingly, NV716 also reduces motility, virulence factors production, and biofilm formation. NV716 shows a unique and highly promising profile of activity when used alone or in combination with antibiotics against P. aeruginosa, combining in a single molecule anti-virulence and potentiator effects. Additional work is required to more thoroughly understand the various functions of NV716.
