Abstract
The molecular action of polyene macrolides with antifungal activity, amphotericin B and natamycin, involves recognition of sterols in membranes. Physicochemical and functional studies have contributed details to understanding the interactions between amphotericin B and ergosterol and, to a lesser extent, with cholesterol. Fewer molecular details are available on interactions between natamycin with sterols. We use solid state 13C MAS NMR to characterize the impact of amphotericin B and natamycin on mixed lipid membranes of DOPC/cholesterol or DOPC/ergosterol. In cholesterol-containing membranes, amphotericin B addition resulted in marked increase in both DOPC and cholesterol 13C MAS NMR linewidth, reflecting membrane insertion and cooperative perturbation of the bilayer. By contrast, natamycin affects little either DOPC or cholesterol linewidth but attenuates cholesterol resonance intensity preferentially for sterol core with lesser impact on the chain. Ergosterol resonances, attenuated by amphotericin B, reveal specific interactions in the sterol core and chain base. Natamycin addition selectively augmented ergosterol resonances from sterol core ring one and, at the same time, from the end of the chain. This puts forward an interaction model similar to the head-to-tail model for amphotericin B/ergosterol pairing but with docking on opposite sterol faces. Low toxicity of natamycin is attributed to selective, non-cooperative sterol engagement compared to cooperative membrane perturbation by amphotericin B.
Highlights
Amphotericin B and natamycin belong to the class of macrolide polyene antibiotics, which are used to prevent and treating opportunistic fungal infections, as well as in the control of food spoilage
High resolution solid state 13C magic angel spinning (MAS) NMR from natural abundance 13C is a useful tool for investigating drug-target interactions in lipid membranes at the molecular level
We have examined the impact of amphotericin B or natamycin addition on mixed membranes of DOPC/cholesterol or ergosterol
Summary
Amphotericin B and natamycin belong to the class of macrolide polyene antibiotics, which are used to prevent and treating opportunistic fungal infections, as well as in the control of food spoilage Both antimycotic compounds are membrane-active and have been shown to interact with ergosterol (Gabrielska et al, 2006; Matsuoka et al, 2006). Because the channel formation involves eight amphotericin B molecules and eight sterols, Baginski group (Baginski et al, 2002) have speculated that small differences in sterol affinity cumulate and become significant enough to trigger specificity Their molecular simulations showed that channels formed with ergosterol are bigger than those formed with cholesterol, greatly affecting the ion permeability
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