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

Abstract

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.

Syntheses and structure–membrane active antimicrobial activity relationship of alkylamino‐modified glucose, maltooligosaccharide, and amylose

“…To examine the effect of the molecular scaffold, a pentylamino group was introduced into glucose, maltose, maltooctaose, and amyloses as the antimicrobial group on the γ‐CD disrupted bacterial membrane . To attach the pentylamino groups onto each sugar, a microwave (MW)‐assisted Huisgen 1,3‐dipolar cycloaddition reaction known as the click chemistry reaction was adopted, which enabled polyfunctionalization of the CD molecule . The maltooctaose derivative 3 was synthesized as shown in Scheme a.…”

Chemical Modification of Cyclodextrin and Amylose by Click Reaction and Its Application to the Synthesis of Poly-alkylamine-Modified Antibacterial Sugars

“…17) Correlation of the hemolysis of rabbit red blood cell by CDs with log P values of the corresponding substituted glucose of CDs 8-21 is shown in Fig. 4.…”

“…16,17) In the case of natural antibacterial peptides, the positively charged amino groups interact with negatively charged bacterial cell membranes, and their hydrophobic groups interact with polar lipid acyl chains in the membrane, which leads to bacterial membrane disruption and the inhibition of bacterial proliferation. Therefore, the introduction of both poly-amino moieties and poly-hydrophobic moieties onto the CD molecule is necessary for its antibacterial action.…”

Cyclodextrins: A Weapon in the Fight Against Antimicrobial Resistance

“…66 A recent study has correlated antimicrobial activity with the CD molecules' hydrophobicity/hydrophilicity balance. 67 These authors surveyed the hydrophobicity (based on partition coe±cient logarithm (log P)) and antimicrobial activity (based on MIC values) of a series of polyalkyamino CDs. A relatively hydrophilic CD (log P < À0:1) may interact with the bacterial cell membrane's anionic surface, while a relatively hydrophobic CD (log P > 0:1) may disturb the surface interaction, as a result only balanced derivatives can disrupt the bacterial membrane.…”

“…A study has suggested that the di®erences in the cell membrane and lipid molecules of Gram-positive and Gram-negative bacteria may contribute to the varied antimicrobial activities of CDs. 67 A little more hydrophobicity appeared to be essential for a CD interacting with the Gram-negative E. coli membrane, more so than for interacting with the Gram positive B. subtilis membrane. Increasing hydrophobicity may increase antimicrobial activity but is associated with an increase in hemolytic activity.…”