Multifunctional nanoassemblies target bacterial lipopolysaccharides for enhanced antimicrobial DNA delivery

Costanza Montis, Pierre Joseph, Chiara Magnani, Alejandro Marín-Menéndez, Francesco Barbero, Amalia Ruiz Estrada, Ridvan Nepravishta, Jesus Angulo, Alice Checcucci, Alessio Mengoni, Christopher J. Morris, Debora Berti

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The development of new therapeutic strategies against multidrug resistant Gram-negative bacteria is a major challenge for pharmaceutical research. In this respect, it is increasingly recognized that an efficient treatment for resistant bacterial infections should combine antimicrobial and anti-inflammatory effects. Here, we explore the multifunctional therapeutic potential of nanostructured self-assemblies from a cationic bolaamphiphile, which target bacterial lipopolysaccharides (LPSs) and associates with an anti-bacterial nucleic acid to form nanoplexes with therapeutic efficacy against Gram-negative bacteria. To understand the mechanistic details of these multifunctional antimicrobial-anti-inflammatory properties, we performed a fundamental study, comparing the interaction of these nanostructured therapeutics with synthetic biomimetic bacterial membranes and live bacterial cells. Combining a wide range of experimental techniques (Confocal Microscopy, Fluorescence Correlation Spectroscopy, Microfluidics, NMR, LPS binding assays), we demonstrate that the LPS targeting capacity of the bolaamphiphile self-assemblies, comparable to that exerted by Polymixin B, is a key feature of these nanoplexes and one that permits entry of therapeutic nucleic acids in Gram-negative bacteria. These findings enable a new approach to the design of efficient multifunctional therapeutics with combined antimicrobial and anti-inflammatory effects and have therefore the potential to broadly impact fundamental and applied research on self-assembled nano-sized antibacterials for antibiotic resistant infections.
Original languageEnglish
Article number111266
JournalColloids and Surfaces B: Biointerfaces
Early online date26 Jul 2020
Publication statusPublished - Nov 2020

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