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.