Rule of Hydrophobicity/Hydrophilicity Balance in Membrane-Disrupting Antimicrobial Activity of Polyalkylamino Cyclodextrins Synthesized via Click Chemistry

Emergence of drug-resistant bacterial pathogens and the concurrent demand for new antibiotics has led to membrane-active antimicrobial cyclodextrin (CD) development. CDs contain polyalkylamino groups; molecule polyfunctionalization was achieved via a click reaction. A survey using CDs with systematically varied functionalities clarified the unique correlation of their antimicrobial activity with the molecules' hydrophobicity/hydrophilicity balance. The optimum hydrophobicity of the membrane-active molecule was specific to bacterial strains and animal cells, leading to selective toxicity against bacteria including multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus. The results demonstrate that CDs have a good molecular scaffold to pursue rationally designed structures with a desired activity for new antibiotic development.