Two antibacterial nalidixate calixarene derivatives in cholesterol monolayers: Molecular dynamics and physicochemical effects

• Cholesterol modulates the properties of nalidixate substituted calixarenes.
• Hydration of calixarene headgroups decreases in the presence of cholesterol.
• Cholesterol plays a role in the transfer of calixarene prodrugs across membrane.

The interaction of two antibacterial calixarene derivatives with cholesterol, a eukaryotic cell membrane lipid, was investigated with the aim to get more insight in the potential advers effects on our cells. The derivatives used had one or two nalidixic acid arms grafted on the lower rim of the calixarene aromatic crown. Monomolecular films spread at the air-water interface were used as model lipid membranes. Pure cholesterol and pure calixarene derivatives, as well as binary cholesterol – calixarene derivative mixtures were studied using surface pressure measurements, polarization-modulation infrared reflection absorption spectroscopy and molecular dynamics simulations. The properties of the mixed monolayers were described quantitatively using thermodynamic models.The analysis of surface pressure-area isotherms of mixed monolayers shows that cholesterol may form homogenous but metastable domains with both nalidixate derivatives. This phenomenon is more clearly observed with mono-substituted calixarene. A detailed modeling analysis indicates that cholesterol favors dehydration of the calixarene polar headgroups and transfer of the derivatives from the aqueous to the gas phase. This effect, more pronounced in the case of the monosubstituted calixarene, can be linked to the hydrophobic interaction with cholesterol. This observation may be useful for developing new calixarene derivatives allowing us to control disease-causing bacteria without harming our own cells.

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