There is a great need on the development of new antibiotics to combat antibiotic-resistant pathogens, which currently cause serious public health issues including hospital-acquired infections In nature, many living species have antimicrobial peptides (AMPs), which is found to be effective against a wide spectrum of pathogens with minimized risk of resistance development. AMPs express their antimicrobial activity through the disruption of bacterial membranes. AMPs form a macroscopic facially-amphiphilic structure on their α-helical backbone where cationic and hydrophobic amino acid residues are segregated in each face. In this study, we have designed and synthesized a series of synthetic antimicrobial agents by mimicking the amphiphilic nature of AMPs by employing a macrocyclic molecular framework. To adopt the amphiphilicity to calixarene, cationic side chains which recognize negatively-charged bacterial membrane were introduced to a hydrophobic calixarene via alkyl space group. We have designed a variety of the calixarene derivatives that differ in the special orientation in the cationic group and sidechain flexibility. The cationic calixarene derivatives found to be active against various type of bacterial strains including gram-negative E. coli, as gram-positive S. aureus and fungus C. albicans. It is noteworthy that the geometry of amphiphilic structure seems to be important for antimicrobial activity; the calixarene, which has segregated cationic group on one side displayed significantly higher activity than that with separated cationic groups against calixarene backbone. We confirmed that E. coli did not develop resistance against the calixarene derivatives where the resistance against conventical antibiotics (Ciprofloxacin) was developed. Model membrane study using fluorescent dye-entrapping liposome clarified that the calixarene derivatives disrupts lipid membranes depending on their composition. In conclusion, we have demonstrated macrocyclic calixarene is a potential material to design a membrane-active antimicrobial agent, which mimics natural AMPs. We expect that macrocyclic calixarene will provide an insight to design resistance-free membrane-active antimicrobial materials.

Cationic calixarene derivative as a membrane-active antimicrobial agent

2019 Spring National Meeting

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