The alarming and prevailing antibiotic resistance crisis urgently calls for innovative “outside of the box” antibacterial agents, which can differ substantially from conventional antibiotics. In this context, we have established antibacterial candidates based on dynamic supramolecular dendrimer nanosystems self-assembled with amphiphilic dendrimers composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing distinct terminal functionalities. Remarkably, the amphiphilic dendrimer with amine terminals exhibited strong antibacterial activity against both Gram-positive and Gram-negative as well as drug-resistant bacteria, and prevented biofilm formation. Multidisciplinary studies combining experimental approaches and computer modelling together demonstrate that the dendrimer interacts and binds via electrostatic interactions with the bacterial membrane, where it becomes enriched and then dynamically self-assembles into supramolecular nanoassemblies for stronger and multivalent interactions. These, in turn, rapidly promote the insertion of the hydrophobic dendrimer tail into the bacterial membrane thereby inducing bacterial cell lysis and constituting powerful antibacterial activity. Our study presents a novel concept for creating nanotechnology-based antibacterial candidates via dynamic self-assembly and offers a new perspective for combatting recalcitrant bacterial infection.
Bibliographical noteFunding Information:
This work was supported by the French National Research Agency under the framework of the ERA-NET EURONANOMED European Research projects ‘TARBRAINFECT’ (LP) and ‘antineuropatho’ (LP), the Chief Scientist office of the Israeli Ministry of Health grant number 3-17903 in the framework of EuroNanoMed 3 European Research project ‘antineuropatho’ (ZH), EU H2020 Research and Innovation program NMBP “SAFE-N-MEDTECH” (2019-2023) (grant agreement No. 814607, LP, BR), AMIDEX d'Aix-Marseille Université (LP), the Ligue Nationale Contre le Cancer (LP, ZL) and China Scholarship Council (LD). This article/publication is based upon work from COST Action CA 17140 “Cancer Nanomedicine from the Bench to the Bedside” supported by COST (European Cooperation in Science and Technology).
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