Abstract
We have characterized and compared the structures of ergosterol- and cholesterol-containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes before and after interaction with the amphiphilic antifungal drug amphotericin B (AmB) using neutron reflection. AmB inserts into both pure POPC and sterol-containing membranes in the lipid chain region and does not significantly perturb the structure of pure POPC membranes. By selective per-deuteration of the lipids/sterols, we show that AmB extracts ergosterol but not cholesterol from the bilayers and inserts to a much higher degree in the cholesterol-containing membranes. Ergosterol extraction by AmB is accompanied by membrane thinning. Our results provide new insights into the mechanism and antifungal effect of AmB in these simple models of fungal and mammalian membranes and help understand the molecular origin of its selectivity and toxic side effects.
Highlights
Among clinically used antifungal treatments, amphotericin B (AmB), an amphiphilic macrocyclic polyene, is remarkable because of its broad spectrum of activity against different organisms, and only low frequency of resistance [1,2,3]
It is accepted that AmB acts by preferentially binding to ergosterol [4,5], which is present in fungal cell membranes, over the cholesterol found in mammalian membranes [6,7], which forms the basis of its fungal specificity
In order to understand the changes due to AmB interaction with the bilayers, neutron reflectometry (NR) data were recorded in the same solvent contrasts before and after interaction with the drug. hPOPC, its per-deuterated version d82POPC [22], ergosterol, per-deuterated d44ergosterol, and cholesterol were used in order to distinguish between the sterols, the lipids, and the AmB
Summary
Among clinically used antifungal treatments, amphotericin B (AmB), an amphiphilic macrocyclic polyene, is remarkable because of its broad spectrum of activity against different organisms, and only low frequency of resistance [1,2,3]. Whether or not this difference in affinity is related to differences in the mechanism of AmB binding to membranes containing different sterols is still an open question, as is the role and importance of the membrane phospholipid composition. This could be important as AmB has a relatively high toxicity that is often dose-limiting in its clinical applications, and this has been proposed to be due to its interaction with cholesterol-containing human host cell membranes. The proposed ergosterol removal, and in particular its effect on the structure of the fungal cell membranes has not been directly investigated
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