Theoretical study of the complexation of amphotericin B with sterols

Langlet, J.; Bergès, Jacqueline; Caillet, J.; Demaret, Jean-Philippe

doi:10.1016/0005-2736(94)90235-6

Cited by 37 publications

(26 citation statements)

References 31 publications

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“…These claims were partially verified on the basis of a conformational analysis of AmB [24][25][26][27] and the primary complex [12], which demonstrated that due to steric reasons there is low probability of existence of such Silberstein's conformational analysis of the channel demonstrated the presence of the 3βOH-2'OH hydrogen bond [23]. During the simulations of our system orientation of the sterol molecule resulted from relatively intensive H-bonding of 3βOH and polar fragments of the antibiotic molecule (up to 80% of the simulation time).…”

Section: Discussionmentioning

confidence: 93%

“…In all probability there are more than one species having various properties and dynamics [8]. It was postulated that the systems which consist of more than two molecules can be more stable as compared to the binary complexes [12].…”

Section: Discussionmentioning

confidence: 99%

“…The authors calculated energies and obtained possible structures of the antibiotic-sterol complex (1:1 stoichiometry). However, constrains needed to keep the method numerically effective almost completely "froze" the system and reduced the study to a kind of rigid conformational analysis of limited area of phase space [12]. In addition, raw energy calculations of 2:1 complexes were there presented.…”

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confidence: 99%

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Molecular modeling of amphotericin B–ergosterol primary complex in water II

Baran

Borowski²,

Mazerski³

2009

Biophysical Chemistry

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The work presented is a part of our continual study on the behavior of the polyene macrolide antibiotic amphotericin B (AmB) complexes with sterols on the molecular level. In contrast to the previously researched AmB-ergosterol binary complex, the AmB-ergosterol-AmB aggregates simulated of 2:1 stoichiometry retain significantly higher stability and relatively rigid, "sandwich" geometry. Van der Waals forces with a considerable share of the electrostatic interactions are responsible for such behavior. System of the intermolecular hydrogen bonds also seems to be of notable importance for the complex's structure preservation. The most energetically favored geometries match fairly close the geometric criteria and the network of interactions postulated in the contemporary hypothetical and computational models of antibiotic-sterol complexes. On the basis of works previously published and the present study novel hypotheses on the AmB selectivity towards sterols varying in chemical structure and on the possible mechanisms of channel structure formation were presented.A

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular modeling of amphotericin B–ergosterol primary complex in water II

Baran

Borowski²,

Mazerski³

2009

Biophysical Chemistry

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“…This antifungal agent possesses a hydrophobic part (hydrocarbon chain) and a hydrophilic part (polyhydroxyl chain); its amphipathic properties allow interactions with the membrane after diffusion through the yeast cell wall. Its interaction with membrane constituents (14,16,18) provokes the formation of pores responsible for several reactions, such as lipid oxidations and peroxidations, inhibition of membrane enzymes (3, 4), osmotic shocks, and, finally, cell death (32).…”

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confidence: 99%

Amphotericin B Resistance and Membrane Fluidity in Kluyveromyces lactis Strains

Younsi

Ramanandraibe

Bonaly

et al. 2000

Antimicrob Agents Chemother

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The membrane fluidity of reduced-amphotericin B (AmB)-sensitivity Kluyveromyces lactis mutant strain is higher than that of the wild-type K. lactis strain. After culture of the K. lactis and K. lactis mutant cells in the presence of subinhibitory doses of AmB (10 and 125 mg/liter, respectively), the plasma membranes of both yeast strains also showed a higher fluidity than did those of control cells. High membrane fluidity was associated with changes in the structural properties of the membranes. Culture of the K. lactis and K. lactis mutant cells in the presence of AmB induced changes in membrane lipid contents. In particular, phospholipid contents were increased in both strains treated with AmB, compared with their corresponding counterparts. As a result, the sterol/phospholipid ratio decreased. The relative proportion of monounsaturated fatty acids also increased after AmB treatment. The saturated fatty acid/monounsaturated fatty acid ratio decreased in K. lactis and K. lactis mutant cells treated with AmB but also in K. lactis mutant control cells compared to that in the K. lactis wild strain. These changes in lipid composition explain the higher fluidity, which could represent a process of metabolic resistance of the yeasts to AmB.Antifungal heptaen amphotericin B (AmB) is presently considered the "gold standard" for the intravenous chemotherapy of deep fungal infections in spite of its secondary effects (24). This antibiotic has been a therapeutic agent since 1956, but its mode of action at the molecular level has not been totally elucidated. Various interaction models with membrane sterols have been proposed. However, the most recent models are based on the formation of stable complexes not only with sterols but also with membrane phospholipids whose interactions induce pore formation (1, 6).AmB was isolated from Streptomyces nodosus cultures by Gold et al. (9). It is a polyene belonging to the macrolide family, and its molecular conformation is closed to phospholipid molecules. This antifungal agent possesses a hydrophobic part (hydrocarbon chain) and a hydrophilic part (polyhydroxyl chain); its amphipathic properties allow interactions with the membrane after diffusion through the yeast cell wall. Its interaction with membrane constituents (14,16,18) provokes the formation of pores responsible for several reactions, such as lipid oxidations and peroxidations, inhibition of membrane enzymes (3, 4), osmotic shocks, and, finally, cell death (32).Yeast resistance to antifungal agents, mainly azol derivatives, is a well-known phenomenon. Yeast cells with reduced sensitivity to AmB have been isolated from patients (24, 29). Horsburgh et al. (13) and Hakkou et al. (11) also isolated a Candida lusitaniae strain and a Kluyveromyces lactis strain, respectively, with reduced sensitivity to AmB. The reduced sensitivity of the strains either may stem from changes in the membrane chemical properties which may result from mutations or may be induced by the antifungal agent itself. The alterations of the membrane may al...

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“…Even though they are expected to play an important structural role, current knowledge of hydrogen bonding in the channel complex is very limited. Unfortunately, experimental studies cannot easily reach this level of detail, and past theoretical studies have used only simple representations such as isolated molecules or AmB/AmB or AmB/sterol molecular pair complexes (10,12,21).…”

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confidence: 99%

Molecular Properties of Amphotericin B Membrane Channel: A Molecular Dynamics Simulation

1997

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SUMMARYAmphotericin B is a powerful but toxic antifungal antibiotic that is used to treat systemic infections. It forms ionic membrane channels in fungal cells. These antibiotic/sterol channels are responsible for the leakage of ions, which causes cell destruction. The detailed molecular properties and structure of amphotericin B channels are still unknown. In the current study, two molecular dynamic simulations were performed of a particular model of amphotericin B/cholesterol channel. The water and phospholipid environment were included in our simulations, and the results obtained were compared with available experimental data. It was found that it is mainly the hydrogen bonding interactions that keep the channel stable in its open form. Our study also revealed the important role of the intermolecular interactions among the hydroxyl, amino, and carboxyl groups of the channel-forming molecules; in particular, some hydroxyl groups stand out as new "hot spots" that are potentially useful for chemotherapeutic investigations. Our results also help to clarify why certain antibiotic derivatives, with a blocked amino group, are less active. We present a hypothesis for the role of membrane lipids and cholesterol in the channel.AmB is a polyene macrolide antibiotic that is widely used in the treatment of systemic fungal infections (1) (Fig. 1, top). Despite its long clinical history, the molecular antifungal action of AmB is not well understood (2, 3). According to the most widely accepted mechanism, AmB molecules interact with membrane sterols to form channels (2-5). The channels are responsible for the leakage of monovalent ions, particularly K ϩ , and other small molecules from the cell. The resulting irregular ionic distribution eventually causes cell death. The chemotherapeutic use of AmB is based on the higher affinity of this antibiotic for ergosterol (principal sterol in fungal cells) than for cholesterol (sterol in mammalian cells) (6). Because it also has high affinity for cholesterol-containing membranes, AmB is quite toxic, and its use in clinical treatment is limited to rather severe cases.To reduce the toxic features of this powerful drug, its antifungal chemotherapeutic properties should be elucidated more precisely. Many experimental efforts (3, 7) designed to achieve a comprehensive understanding of the membranous AmB/sterol channels have shown that these channels are difficult to study; thus, there is little information available for the molecular level, and the channel structure remains unknown. In addition to experiments, in several recent theoretical studies (8 -14), the focus has been on the isolated molecular properties of AmB or sterols (8 -12). In some of these studies, the channel structure was also considered (13-15); however, only simple molecular mechanics or electrostatic calculations without proper treatment of the membrane/water environment were used. Ultimately, experimental efforts together with molecular modeling approaches should lead to a more complete understanding of the molecular ...

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Theoretical study of the complexation of amphotericin B with sterols

Cited by 37 publications

References 31 publications

Molecular modeling of amphotericin B–ergosterol primary complex in water II

Molecular modeling of amphotericin B–ergosterol primary complex in water II

Amphotericin B Resistance and Membrane Fluidity in Kluyveromyces lactis Strains

Molecular Properties of Amphotericin B Membrane Channel: A Molecular Dynamics Simulation

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