Antibiotic resistance has attracted increasing public attention in recent years, owing to the occurrence of multidrug-resistant bacterial strains. The World Health Organization identified antimicrobial resistance as one of the three greatest threats facing mankind in the 21st century. Therefore, there is an urgent need to develop new antibiotics with unconventional molecular approaches on fighting bacterial infections and drug-resistance. Daptomycin as the first clinically approved lipopeptide antibiotic is notably active against multidrug-resistant pathogens. The consensus mechanism of daptomycin involves disruption of the bacterial cell membrane by forming transmembrane channels, which allows the flow of ions out of the cell and lead to the depolarization of the membrane and cell death. As the membrane interaction doesn't involve specific cellular or membrane targets, the probability of resistance development in bacteria is minimal. Inspired by daptomycin, several diverse families of synthetic, membrane-active macromolecules were developed to form channels within membrane bilayers. Despite significant enthusiasm, there are intrinsic drawbacks associated with these synthetic systems, including low-to-moderate activity, high cellular toxicity, and inconvenient optimization. In our preliminary study, supramolecular concentric hexagons displayed high antimicrobial activity against Gram- positive pathogens and negligible toxicity to eukaryotic cells through forming transmembrane channels. Compared to daptomycin, the synthesis is easier for scaling up and the large surface area of supramolecules allows effective interaction with bacterial membrane to ensure channel forming. These findings may pave a new avenue in the seeking of the new generation of antimicrobial agents. Our long-term goal is to develop a new class of supramolecules with novel mechanisms in the treatment of bacterial infectious disease. The objective is to identify more potent analogs of supramolecules, and to investigate their mechanism of action on bacterial membranes. Our central hypothesis is that those 2D supramolecules can assemble into channels with multi-layered structure and distinct pore size inside the bacterial membrane and thus, lead to the leakage of cytoplasmic components and cell death. As such, we propose to accomplish the following specific aims: (1) Design and synthesize novel analogs of previously designed antimicrobial 2D multi-layered metallo- supramolecules; (2) Through structure-function-relationship studies, identify lead supramolecules with specific activity against Gram-positive bacteria; (3) Investigate if forming multilayered channels with distinct pore size in the bacterial membrane is the general bactericidal mechanism. We contend that our work will have a major positive impact, as these studies are highly likely to provide a new class of antibiotic agents with unprecedented mechanisms. In addition, the research will demonstrate the biological potential of metallo- supramolecules, and lead to new biomedical applications to supramolecular chemistry field.
There is an urgent need to develop new antimicrobial agents to fight infections due to emergent antibiotic re- sistance. The major goal of this research is to design, synthesize and investigate a new class of antibacterial biomaterials based on 2D metallo-supramolecules with multilayered structure. We intend to demonstrate that such biomaterials are a promising approach to the development of a new generation of antibiotics with novel mechanism through formation unprecedented multi-layered transmembrane channels with distinct pore size.
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