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The Formation of Amphotericin B Ion Channels in Lipid Bilayers

Fujii, Gary and Chang, Joan-En and Coley, Terry and Steere, Boyd (1997) The Formation of Amphotericin B Ion Channels in Lipid Bilayers. Biochemistry, 36 (16). pp. 4959-4968. ISSN 0006-2960.

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The ability of amphotericin B (AmB) to form ion-permeable channels in cholesterol containing lipid bilayers was studied by UV/visible absorbance, circular dichroism, and fluorescence spectroscopy. Stable liposomes composed of distearoylphosphatidylcholine, cholesterol, distearoylphosphatidylglycerol, and AmB were prepared so that a wide range of AmB concentrations in the bilayer could be studied. Singular value decomposition analysis (Henry & Hofrichter, 1992) of the circular dichroism spectra of AmB at different AmB/lipid ratios suggests that AmB exists primarily in only two states in the bilayer, a “monomeric” state and an “aggregated” state. The transition from the “monomeric” to the “aggregated” state begins to occur at a critical concentration of 1 AmB per 1000 lipids in the membrane and coincides with the appearance of channel activity. The data support the recent theoretical conclusions of Weakliem et al. (1995) which predict that pore formation in the lipid bilayer will occur when the drug molecule concentration exceeds a critical value. At this critical concentration, it is calculated that a minimum number of 16 AmB molecules per liposome are required to observe channel activity. The results are consistent with the sterol-dependent AmB channel models proposed by de Kruijff and Demel (1974), Andreoli (1974), and Khutorsky (1992). To further elucidate the effects of sterol on AmB-mediated channel formation, liposomes were prepared with varying ratios of cholesterol and AmB. At cholesterol mole percentages greater than 1, channel activity was observed to occur at AmB concentrations just above the critical value. Previous reports show that cholesterol forms “tail-to-tail” dimers at mole percentages greater than 2 (Harris et al., 1995). This suggests that formation of the bilayer-spanning channels by AmB is initiated most efficiently when the tail-to-tail dimer of cholesterol is present. Although the structural nature of the AmB channel could not be unambiguously determined, these experiments provide further evidence in support of the widely held view that AmB's primary mechanism of killing fungal cells occurs by forming ion-permeable channels.

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Additional Information:© 1997 American Chemical Society. Received November 22, 1996; Revised Manuscript Received February 10, 1997. Publication Date (Web): April 22, 1997. The authors kindly thank Professors E. Riesler and K. Kantardjieff for use of the CD instruments and NeXstar Pharmaceuticals, Inc., for the amphotericin B lipid powders. We also thank C. Weakliem, Paul G. Schmidt, and Professors F. Szoka, W. A. Goddard, III, and W. Gelbart for helpful discussions.
Issue or Number:16
Record Number:CaltechAUTHORS:20170919-145021162
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Official Citation:The Formation of Amphotericin B Ion Channels in Lipid Bilayers. Gary Fujii, Joan-En Chang, Terry Coley, and Boyd Steere. Biochemistry 1997 36 (16), 4959-4968. DOI: 10.1021/bi962894z
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:81584
Deposited By: Tony Diaz
Deposited On:19 Sep 2017 22:02
Last Modified:03 Oct 2019 18:44

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