Molecular Pharmacology, Vol 1, 190-201, Copyright © 1965 by the American Society for Pharmacology and Experimental Therapeutics

Interaction of Polyene Antibiotics with Subcellular Membrane Systems I. Mitochondria

¹ Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri
² Department of Microbiology, St. Louis University School of Medicine, St. Louis, Missouri

The action of the polyene antibiotics, ascosin, candicidin, amphotericin B, candidin, etruscomycin, filipin, nystatin, and pimaricin, on Neurospora and rat liver mitochondrial succinate-cytochrome c reductase was investigated. Only the ascosin and candicidin preparations inhibited this reaction. Various criteria indicated that both these antibiotic preparations were impure. Thin-layer chromatography of an acetone extract of ascosin revealed the presence of antimycin A. The inhibition of the succinate-cytochrome c reductase by ascosin was not due to the polyene per se, but was a consequence of contamination by antimycin A.

Although mitochondrial function (electron transport, as well as oxidative phosphorylation and ion transport) is not affected by these antibiotics, Neurospora mitochondria were able to bind filipin. The antibiotic could be recovered from the mitochondria after extraction with dimethyl formamide. Previous studies have shown that the presence of sterol is a necessary prerequisite for polyene binding to cell membrances. Neurospora mitochondria contain ergosterol although less than the microsomal fraction, which is partly derived from the cell membrane. The above findings indicate that the presence of sterol may not be sufficient to confer polyene sensitivity to a membrane system. Mitochondria have a much higher phospholipid: sterol ratio than cell membranes, suggesting that the relative concentration of these lipids may be an important factor in determining polyene sensitivity.

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ACKNOWLEDGMENTS This research has been supported by U.S.P.H.S. grants AI-05114 and Research Career Development Award 5-K3-AI-6388 (to SCK), and grant AI-03046 (to MMW). We are also indebted to Professor L. L. M. van Deenen, der Rijksuniversiteit, Utrecht, The Netherlands, for many helpful discussions.