Synergistic approaches for combating the pathogen Acinetobacter baumannii: dynamic constitutional frameworks and pillararene-based self-assembled drug delivery systems

In this study, we developed dynamic and supramolecular structures to combat the highly resistant pathogen Acinetobacter baumannii. This Gram-negative ESKAPE pathogen has a strong ability to form biofilms, which raises a key but challenging question: how to discover molecules active on both planktonic bacteria and their biofilms. To achieve this, we introduce two non-covalent ordered systems with antimicrobial and antibiofilm effects based on two distinct types of interactions: dynamic covalent bonding and supramolecular self-assembly. We discovered and optimized potent systems based on a cationic dynamic constitutional framework and a pillararene–antibiotic self-assembled drug delivery system through a synergistic screening process. Our screening methodology is based on searching for the synergistic effect of subcomponents to determine their optimal combinations and optimize their antibacterial potency. Crucially, our synergistic screening approach not only enables the rapid optimization of component combinations but also demonstrates the potential to generate potent bioactivity from individually inactive molecules and transform antibiotics with poor antibiofilm efficacy into highly active supramolecular systems, offering a significant advancement in combating challenging pathogens, such as A. baumannii.