Cationic Molecular Umbrellas as Antibacterial Agents with Remarkable Cell-Type Selectivity
| Autor: | Ao Chen, Benjamin R. Carone, Matthew R. Necelis, Edmund F. Palermo, Apostolos A. Karanastasis, Kaitlyn R. Casey, Gregory A. Caputo |
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| Rok vydání: | 2020 |
| Předmět: |
Dendrimers
Staphylococcus aureus Materials science Cell Survival Microbial Sensitivity Tests 02 engineering and technology 010402 general chemistry 01 natural sciences Small Molecule Libraries Structure-Activity Relationship Surface-Active Agents chemistry.chemical_compound Dendrimer Escherichia coli Humans General Materials Science Alkyl Antibacterial agent chemistry.chemical_classification Molecular Structure Cell Membrane Cationic polymerization 021001 nanoscience & nanotechnology Combinatorial chemistry Anti-Bacterial Agents 0104 chemical sciences Monomer chemistry beta-Alanine 0210 nano-technology Selectivity Antibacterial activity HeLa Cells Macromolecule |
| Zdroj: | ACS Applied Materials & Interfaces. 12:21270-21282 |
| ISSN: | 1944-8252 1944-8244 |
| DOI: | 10.1021/acsami.9b19076 |
| Popis: | We synthesized a combinatorial library of dendrons that display a cluster of cationic charges juxtaposed with a hydrophobic alkyl chain, using the so-called "molecular umbrella" design approach. Systematically tuning the generation number and alkyl chain length enabled a detailed study of the structure-activity relationships in terms of both hydrophobic content and number of cationic charges. These discrete, unimolecular compounds display rapid and broad-spectrum bactericidal activity comparable to the activity of antibacterial peptides. Micellization was examined by pyrene emission and dynamic light scattering, which revealed that monomeric, individually solvated dendrons are present in aqueous media. The antibacterial mechanism of action is putatively driven by the membrane-disrupting nature of these cationic surfactants, which we confirmed by enzymatic assays on E. coli cells. The hemolytic activity of these dendritic macromolecules is sensitively dependent on the dendron generation and the alkyl chain length. Via structural optimization of these two key design features, we identified a leading candidate with potent broad-spectrum antibacterial activity (4-8 μg/mL) combined with outstanding hemocompatibility (up to 5000 μg/mL). This selected compound is >1000-fold more active against bacteria as compared to red blood cells, which represents one of the highest selectivity index values ever reported for a membrane-disrupting antibacterial agent. Thus, the leading candidate from this initial library screen holds great potential for future applications as a nontoxic, degradable disinfectant. |
| Databáze: | OpenAIRE |
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