Interaction of selected alkoxy naringenin oximes with model and bacterial membranes

Naringenin is a flavonoid found in many fruits and herbs, most notably in grapefruits. In recent years, this compound and its derivatives have been of great interest due to their high biological activity, including fungicidal and bactericidal effects, also in relation to multidrug-resistant bacteria. Membrane interactions of naringenin oxime (NO) and its 7-O-alkyl (7-alkoxy) derivatives, such as methyl (7MENO), ethyl (7ETNO), isopropyl (7IPNO), n-butyl (7BUNO) and n-pentyl (7PENO) were studied. Thermotropic properties of model membranes were investigated via differential scanning calorimetry (DSC), the influence on lipid raft mimicking giant unilamellar vesicles (GUVs) via fluorescence microscopy, and membrane permeability via measuring calcein leakage from liposomes. Molecular calculations supplemented the study. The influence of naringenin oximes on two strains of multidrug resistant bacteria: Staphylococcus aureus KJ and Enterococcus faecalis 37VRE was also investigated. In DSC studies all compounds reduced the temperature and enthalpy of main phase transition and caused disappearing of the pretransition. NO was the least active. The reduction in the area of surface domains in GUVs was observed for NO. Compounds NO and 7BUNO resulted in very low secretion of calcein from liposomes (permeability < 3 %). The highest results were observed for 7MENO (88.4 %) and 7IPNO (78.5 %). When bacterial membrane permeability was investigated all compounds caused significant release of propidium iodide from S. aureus (31.6-87.0 % for concentration 128 μg/mL). In the case of E. faecalis, 7ETNO (75.7 %) and NO (28.8 %) were the most active. The rest of the tested compounds showed less activity (permeability < 13.9 %). The strong evidence was observed that antibacterial activity of the tested compounds may be associated with their interaction with bacterial membrane.