Mixed Monolayers of Amphotericin B−Dipalmitoyl Phosphatidyl Choline:  Study of Complex Formation

Abstract

Mixed Langmuir monolayers of amphotericin B (AmB) and dipalmitoyl phosphatidyl choline (DPPC) were investigated by recording surface pressure-area (π-A) isotherms in addition to Brewster angle microscopy. The analyses of π-A and compressional modulus curves indicate the existence of interactions in the AmB-DPPC system; the greatest were found to occur for a ca. 2:1 AmB/DPPC mixture. For this mixed monolayer (XAmB ) 0.66), the formation of a stable complex, composed of two horizontally oriented AmB molecules and one DPPC molecule in a vertical position, is suggested. For mixtures containing AmB in excess as compared to the stoichiometric mixture for the complex formation (XAmB > 0.66), the filmforming components are miscible and the mixed monolayer consists of AmB-DPPC complexes together with horizontally (at surface pressures below the first transition) or vertically (at pressures above this transition) oriented free AmB molecules. On the other hand, mixtures of AmB-DPPC complex and DPPC in excess (at XAmB < 0.66) were found to be miscible at surface pressures below the second transition. However, the system becomes immiscible at higher surface pressures.

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

“…This would be consistent with the proposal that specific interactions between the charged functional groups of AmB and the zwitterionic PC headgroups (Fig. 1D) (15)(16)(17)(18)(19) help anchor AmB to the membrane (12,13). To test this proposal, we first determined the relative binding of AmB and its derivatives to yeast cells (58).…”

“…1C) (8,(11)(12)(13)(14). Second, one or both of these functional groups are proposed to form critical polar interactions with phospholipid headgroups either to "anchor" AmB to the membrane (12,13) and/or to promote channel formation (15)(16)(17)(18)(19) (Fig. 1D).…”

“…Despite more than half a century of intensive study, however, the mechanism of action of AmB is poorly understood. Even the most basic components of the leading model remain unclear, including the structure/function relationships that underlie channel self-assembly (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), the importance of AmB/phospholipid interactions (12,13,(15)(16)(17)(18)(19), the role of membrane sterols in forming ion channels (5-13, 15, 20-40), and even whether channel formation is causitively linked to antifungal activity (41)(42)(43).…”

Mixed monolayers involving DPPC, DODAB and oleic acid and their interaction with nicotinic acid at the air–water interface

“…This explains the enormous interest and the high number of studies reporting on this phospholipid and their mixtures with a large range of other components. Some examples are the relevant studies on the molecular interactions of DPPC with cholesterol (Albrecht et al, 1981;Kim et al, 2001), fatty acids (Bringezu et al, 2001;Cockshutt et al, 1991), proteins (Bringezu et al, 2002;Chang et al, 2000) and in multicomponents mixed monolayers (Miñones et al, 2002;Ding et al, 2003).…”

Interactions between membrane sterols and phospholipids in model mammalian and fungi cellular membranes — A Langmuir monolayer study

“…To understand their role in the polyenes mechanism of action, it is of utmost importance to study the interactions between the antibiotic and phospholipids in the presence of sterols. Until now, the Langmuir monolayer technique was applied to examine the interactions between polyene antibiotics and either sterol [20,21] or phospholipids [22,23]. However, to understand the complex mechanism of action of the polyene antifungal it is necessary to study the interactions between the antibiotic and the lipidic components of the fungi and mammalian cellular membranes (phospholipids and sterols).…”