Penetration of Lipid Monolayers by Polyene Antibiotics CORRELATIOS WITH SELECTIVE TOXICITY AND MODE OF ACTION*

Previous studies have shown that polyene antibiotics alter permeability in sensitive fungi and thus lead to the loss of essential cytoplasmic constituents, which ultimately culminates in cell death (l-3). Subsequent investigations have led to the contention that the selective toxicity of the polyene antibiotics is due to interaction with a component present only in the membrane of sensitive organisms. This hypothesis lvas based on the observation that whole cells, protoplasts, and isolated membrane fractions of polyene-sensitive fungi bind appreciable quantities of nystatin, amphotericin B, and filipin, whereas cells, protoplasts, and membrane fractions of polyene-insensitive bacteria do not bind any of the antibiotics (4, 5). Several lines of evidence support the conclusion that sterol may be this unique component. (a) Sterols can prevent the inhibitory act.ion of polyene antibiotics on fungal growth (6), and spectrophotometric studies have provided evidence for combination between the antibiotics and cholesterol or ergosterol (7). (b) All polyene-sensitive organisms (fungi, protozoa, higher algae, pleuropneumonia-like organisms, flatworms, snails, and mammalian erythrocytes) contain sterols, whereas polyeneinsensitive organisms (bacteria, blue-green algae) do not. (c) The ability of membrane fractions from Neurospora crassa to bind nystatin is completely abolished by extraction with organic solvents, and antibiotic-binding capacity can be partially restored by addition of ergosterol (5). (d) A close correlation exists between the ability to bind nystat’in and the ergosterol content of various subcellular fractions from Saccharomyces cerevisiae (8). (e) Digitonin, a “sterol-specific” complesing agent that mimics the action of the polyenes on protozoa and fungi, markedly inhibits polyene uptake by intact cells or isolated membrane fractions (g-11). Recently, Goldfine and Ellis have shown that bacteria in general are not able to synthesize choline derivatives (12). Thus, lecithins also satisfy the requirement of a membrane component present only in polyene-sensitive organisms, and interaction with these lipids may also explain t,he selective toxicity of the antibiotics. Several reports have, in fact, indicated that polyene