Interaction between macrolide antibiotics and model membranes

A possible mechanism of interaction between the macrolide antibiotics studied and phospholipid model membranes is proposed in the last part of this work. Data in literature show that all three antibiotics studied here are characterized by a hydrophobic behaviour. Hydrophobic interaction could be the main interaction between antibiotics and phospholipids.
However, despite the common hydrophobic character, the antibiotics studied showed diferent efects on phospholipid model membranes. Aivlosin was found to be more hydrophobic than other macrolides , even if no previous work comparing the three antibiotics studied here. It is likely Aivlosin inserts deep inside the phospholipid bilayer, due to its high hydrophobic interaction with phospholipids. Recalling the ADE model, this would not induce an area diference between the inner and the outer leafet of the bilayer, avoiding rupture or instability of larger GUVs. The very hydrophobic character of Aivlosin could induce the formation of macromolecular drugphospholipid complexes, in interacting with phospholipid monolayers.

These complexes could intercalate in the monolayer; successive solubilization in the bulk subphase could take place, as the formation of these complexes at the airwater interface would be an outofequilibrium process. In this case, phospholipids could arrange around the hydrophobic Aivlosin molecule with hydrophobic tails inwards and hydrophilic heads outwards, shielding the drug molecule from the water subphase and contemporarly favouring the transferring of the complex in the bulk subphase.
The efect of Aivlosinphospholipid complexes could be seizing part of the phospholipids from the monolayer and, during the intercalation into the monolayer, increasing its rigidity and viscosity. Both Azithromycin and Clarithromycin could bind to the phospholipid bilayer, inserting into the outer membrane layer (at the phospholipid acylchain/polar headgroup interface). Neverthless, their hydrophobic interaction with phospholipid membrane would not be strong enough to allow them to penetrate deeper in the bilayer.