Effect of the polar head structure of polyene macrolide antifungal antibiotics on the mode of permeabilization of ergosterol- and cholesterol-containing lipidic vesicles studied by 31P-NMR.
Natural polyene macrolide antibiotics and their N-acyl and methyl ester derivatives, which differ mainly in their electric net charge, were compared for their ability to increase the ionic permeability of large unilamella vesicles, using the proton-cation exchange method and 31P-NMR spectroscopy. The zwitterionic (amphotericin B, vacidin A) and negatively charged (N-N'-diacetyl vacidin) compounds induced permeability according to an all-or-none process on both cholesterol- and ergosterol-containing membranes. The same mechanism of permeability induction is obtained only on ergosterol-containing vesicles for positively charged antibiotics (perimycin A, vacidin A methyl ester, amphotericin B methyl ester). A different type of action is observed for the latter group of ionophores in cholesterol-containing vesicles. In this case, a progressive proton efflux occurs in which all of the vesicle population is involved. This qualitative difference in the kinetics of ionic fluxes induced by antibiotics without a free carboxyl group in cholesterol-containing as compared to ergosterol-containing membranes was ascribed to differences in polyene-sterol interactions as well as in the life time of the ionic path formed. This difference may provide a basis for the improvement of selective toxicity of this group of antifungal agents by rational modifications.
D000935:Antifungal Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D004875:Ergosterol / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007476:Ionophores / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids / Q000378:metabolism*; D010539:Permeability; D011090:Polyenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D007476:Ionophores; D008563:Membrane Lipids; D011090:Polyenes; D002784:Cholesterol; D004875:Ergosterol