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PubMed1996

[Effect of orally administered polyene antimycotics on the intestinal colonization with yeasts: possibilities and limitations].

On the basis of intestinal yeast colonization different consequences for therapeutic and prophylactic administration of polyene antimycotics have to be drawn. Immunocompromised neutropenic patients should orally receive polyene antifungal drugs (nystatin or amphotericin B) for a long time during the period of increased risk for systemic candidosis. The level of daily dosing is dependent on age, physiological status of the gastrointestinal tract, and underlying disease of the patient. In immunocompetent persons the normal commensal yeast flora should not be suppressed by antifungal chemoprophylaxis if no clinical indications are present, because permanent eradication of yeast in the intestinal tract ist not attainable. About 5 to 15 days after finishing the administration of polyene antimycotics the fungi are detectable again in the faeces in low quantities. The influence of orally administered polyene drugs in the intestinal tract may be detected shortly after starting the application. Thus efficient concentrations of nystatin and amphotericin B are continuously present in the faeces 24 to 48 hours after beginning until 2 to 10 days after finishing the administration. During this time the quantity of yeast in the faeces is evidently reduced or not longer detectable by fungal culture. The oral administration of polyene antimycotics for a long time in persons without immunodepression and without heavy intestinal yeast colonization is not justified.

Administration, Oral↗
PubMed1978

Mechanistic studies of polyene enhancement of interferon production by polyriboinosinic-polyribocytidylic acid.

The production of interferon by polyriboinosinic-polyribocytidylic acid [poly(I) . poly(C)] and poly(I) . poly(C)-diethylaminoethyl-dextran in L929 cells was enhanced from 10 to 100 times by polyene macrolides, including amphotericin B (AmB), AmB methyl ester, nystatin, and filipin. AmB and its water-soluble methyl ester were the most effective; retinol, a nonmacrolide polyene, was ineffective. Interferon induction by Newcastle disease virus was not enhanced by AmB. The kinetics of interferon production were not markedly altered by AmB. Polyenes and poly(I) . poly(C)-diethylaminoethyl-dextran did not need to be present on cells simultaneously to enhance interferon production. Pretreatment with polyenes was as effective as simultaneous addition. Even treatment of washed cells, several hours after removal of poly(I) . poly(C)-diethylaminoethyl-dextran, resulted in enhancement of interferon production. AmB did not appear to form a macromolecular complex with poly(I) . poly(C) in that neither the ultraviolet absorption spectrum nor the melting point of poly(I) . poly(C) was altered by mixing with AmB. Isotopic studies indicated that AmB did not enhance binding of poly(I) . poly(C) to cells. Since the macrolide polyenes have been demonstrated to bind to cell membrane sterols with subsequent alterations in membrane permeability barriers, they may enhance interferon production by increasing cell penetration of poly(I) . poly(C).

Animals↗
PubMed1981

Repair of membrane alterations induced in baby hamster kidney cells by polyene macrolide antibiotics.

We studied the correlation between chemical characteristics of 13 polyene macrolide antibiotics and the ability to repair the membrane permeability changes induced by polyenes in BHK-21 cells grown in shaker culture. It had been demonstrated that large-macrolide-ring polyenes with rigid molecules (heptaenes) induced specific membrane permeability pathways which were repaired by the eucaryotic cells under the proper conditions. The influence of environmental conditions on the repair process was examined. Aureofacin trimethylammonium methyl ester derivative was used as a selected representative of polyene macrolides inducing specific pathways. The factors influencing the repair process, monitored by measuring the ability of BHK-21 cells to control K+ membrane transport, were examined during and after cell contact with the antibiotic. We found that the repair process was dependent upon the temperature, the concentration of the antibiotic, time of its contact with cells, potassium concentration in the medium, and availability of an energy source. The repair process occurred in the presence of cycloheximide, which inhibited protein synthesis in BHK-21 cells. Results showed that the repair process plays an important role in mammalian cell recovery from the toxic effects of polyenes.

Animals↗
PubMed1972

Reversal by calcium ions of the growth inhibition of Debaryomyces nicotianae caused by antifungal polyene antibiotics.

Only Debaryomyces nicotianae strain 77, of seven different yeast strains tested, was found to be resistant to heptamycin and other antifungal heptaenes when grown in a rich medium. This strain, however, like the other six, was completely susceptible to these antibiotics in a minimal medium. Addition of yeast extract to the minimal medium abolished the heptamycin effect; calcium ions fully duplicated the effect of yeast extract; Mg(2+) and Mn(2+) were also effective but less so than Ca(2+). Ca(2+) also counteracted the activity of the heptaenes ascosin and trichomycin. Complete reversal of the polyene inhibition by Ca(2+) was obtained if the cation was added simultaneously with the antibiotic; addition of Ca(2+) 2 hr after the polyene was without effect. Addition of Ca(2+) in the absence of the polyene caused a slight, if any, growth stimulation of D. nicotianae 77. Cholesterol also counteracted polyene activity; this was due to the formation of a complex with the antibiotic which prevented the polyene from reaching the site of action-the cytoplasmic membrane. No evidence for complex formation between heptamycin and calcium was found. The importance of Ca(2+) in membrane structure, as evidenced from heptaene studies, is discussed.

Antifungal Agents↗
PubMed2004

Polyene macrolide antibiotic biosynthesis.

Polyenes constitute a large class of natural metabolites produced by giant multifunctional enzymes in a process resembling fatty acid biosynthesis. Like fatty acids, polyene macrolides and other polyketides are assembled by decarboxylative condensations of simple carboxylic acids. But while fatty acid intermediates are fully reduced, polyene macrolide intermediates suffer the suppression of reduction or dehydration reactions at given biosynthetic steps. In the last years, much progress has been made in our understanding of the linear and modular organization of the gene clusters, and the enzymes encoded by them, responsible for the biosynthesis of these macrocyclic metabolites. This know-how about the rules that govern polyene chain growth has provided the basis for the first rational manipulations of these fascinating systems for the production of engineered derivatives and promises a new era of novel polyene development, which will hopefully yield new molecules with improved pharmacological properties.

Antifungal Agents↗
PubMed1990

A screening method for antifungal substances using Saccharomyces cerevisiae strains resistant to polyene macrolides.

Strains of Saccharomyces cerevisiae FL200 capable of growing on a solid medium containing a mixture of polyene macrolide antibiotics (nystatin, 40 micrograms/ml, amphotericin B, 40 micrograms/ml, pimaricin, 150 micrograms/ml and RP9971 antibiotic, 10 micrograms/ml) have been isolated after successive selection steps. The mutant strains, PR13 and PRC24, are 10 to 100 times more resistant than the polyene macrolide antibiotics. When 4% Tween 80 is added to the medium, resistance to these antifungal drugs is further increased. In addition, strain PRC24, derived from strain PR13, is resistant to a non-polyene macrolide antifungal antibiotic, cycloheximide. In contrast, PR13 and PRC24 are both highly susceptible to a large range of compounds, including non-polyenic antifungal, antitumor and antibacterial agents. These particular characteristics make these strains useful for the rapid detection of antifungal compounds of the polyene macrolide and cycloheximide types, as well as for the recognition of antimitotic substances.

Anti-Bacterial Agents↗
PubMedDate not supplied

[Study of the resistance of Candida guilliermondii to polyene antibiotics].

250 Candida guilliermondii strains resistant to the polyene antibiotics nystatin, levorin and amphotericin B were obtained using UV irradiation. When the mutant strains became resistant to one of the polyene antibiotics, their resistance to the other ones changed. Phenotypic analysis showed that the resistance of the strains to polyene antibiotics did not make them susceptible to a rise in osmotic pressure and to a change of the temperature of incubation. Some of the polyene-resistant strains were stained in a medium with methylene blue. Analysis of the sterol composition in the mutants by UV spectroscopy showed that the resistance to polyene antibiotics sometimes involved changes in the sterol composition. Two new UV spectrum types were recorded for the sterols of the mutant strains; they differed from the UV spectrum for the sterols of the parent sensitive strain.

Antifungal Agents↗
PubMed1982

[Trypanosome sensitivity to polyene antibiotics].

Swelling of the plasma membrane is one of the mechanisms of resistance to damages in pathogenic Protozoa. Polyenic antibiotics induce reconstruction of the cytoplasma membrane of unicellular eukaryotic organisms, i. e. fungi and Protozoa by binding the membrane lipids. The effect of 5 heptaene polyenic antibiotics, such as amphotericin B, mycoheptin, levorin, its sodium salt and levoridone on the growth of trypanosomides of Trypanosoma lewisi and Crithidia oncopelti was studied. The MIC and IC50 of these antibiotics were determined. It was found that these antibiotics were inhibitors of the trypanosomide growth and development. Levorin and amphotericin were most active with respect to C. oncopelti and levorin was most active with respect to T. lewisi. Physiological and morphological changes in the trypanosomides induced by the polyenic antibiotics were noted. The effect of levorin and amphotericin B on the content of lipids in the trypanosomide cells was studied. A decrease in the total content of the intracellular lipids due to the effect of the polyenes was shown. Differences in the rate of the inhibitory effect as dependent on the structure of the hydrophile part of the lactone ring of the heptaene polyenic antibiotics were found.

Anti-Bacterial Agents↗
PubMed2000

A complex multienzyme system encoded by five polyketide synthase genes is involved in the biosynthesis of the 26-membered polyene macrolide pimaricin in Streptomyces natalensis.

BACKGROUND: Polyene macrolides are a class of large macrocyclic polyketides that interact with membrane sterols, having antibiotic activity against fungi but not bacteria. Their rings include a chromophore of 3-7 conjugated double bonds which constitute the distinct polyene structure. Pimaricin is an archetype polyene, important in the food industry as a preservative to prevent mould contamination of foods, produced by Streptomyces natalensis. We set out to clone, sequence and analyse the gene cluster responsible for the biosynthesis of this tetraene. RESULTS: A large cluster of 16 open reading frames spanning 84985 bp of the S. natalensis genome has been sequenced and found to encode 13 homologous sets of enzyme activities (modules) of a polyketide synthase (PKS) distributed within five giant multienzyme proteins (PIMS0-PIMS4). The total of 60 constituent active sites, 25 of them on a single enzyme (PIMS2), make this an exceptional multienzyme system. Eleven additional genes appear to govern modification of the polyketide-derived framework and export. Disruption of the genes encoding the PKS abolished pimaricin production. CONCLUSIONS: The overall architecture of the PKS gene cluster responsible for the biosynthesis of the 26-membered polyene macrolide pimaricin has been determined. Eleven additional tailoring genes have been cloned and analysed. The availability of the PKS cluster will facilitate the generation of designer pimaricins by combinatorial biosynthesis approaches. This work represents the extensive description of a second polyene macrolide biosynthetic gene cluster after the one for the antifungal nystatin.

Amino Acid Motifs↗
PubMed1985

Phospholipid enrichment of Saccharomyces cerevisiae and its effect on polyene sensitivity.

Sensitivity to polyene antibiotics, e.g., nystatin, amphotericin B, and filipin, was determined in phosphatidylcholine (PC) or phosphatidylethanolamine (PE) or phosphatidylserine (PS) enriched Saccharomyces cerevisiae cells, using glutamic acid, phenylalanine, glycine, and lysine transport as an index of polyene antibiotic action. As compared with normal cells, phospholipid-enriched cells acquired resistance towards different polyenes. However, the sensitivity of glutamic acid transport towards nystatin remained unaffected in PC-, PE-, or PS-enriched cells. In contrast to nystatin, the other two polyenes were more effective in checking the influx of amino acids. Results demonstrated that the specific enrichment of PC, PE, or PS could selectively protect S. cerevisiae cells from polyene antibiotic action.

Amino Acids↗
PubMed1987

Sterols in Candida albicans mutants resistant to polyene or azole antifungals, and of a double mutant C. albicans 6.4.

Investigations of resistant mutants could help resolve differences and similarities in the action of azole and polyene antifungals whose modes of action are related; both disrupt membrane properties, such as permeability, by interfering with membrane sterols--polyenes by direct binding and azoles by inhibiting their synthesis. Studies of laboratory-derived mutants of Candida albicans which have an altered sterol content and/or an altered sterol composition do not provide evidence for a unified mechanism of polyene resistance. Clinical isolates of azole-resistant C. albicans have an increased or unaltered content of ergosterol and are impermeable to azoles. C. albicans 6.4, a laboratory-derived mutant resistant to both polyenes and azoles, is impermeable to azoles and has an increased content of methylated sterols. This unusual sterol composition resembles that of sensitive strains grown in the presence of azoles and may prevent polyene binding.

Antifungal Agents↗
PubMed2001

Engineered biosynthesis of novel polyenes: a pimaricin derivative produced by targeted gene disruption in Streptomyces natalensis.

BACKGROUND: The post-polyketide synthase biosynthetic tailoring of polyene macrolides usually involves oxidations catalysed by cytochrome P450 monooxygenases (P450s). Although members from this class of enzymes are common in macrolide biosynthetic gene clusters, their specificities vary considerably toward the substrates utilised and the positions of the hydroxyl functions introduced. In addition, some of them may yield epoxide groups. Therefore, the identification of novel macrolide monooxygenases with activities toward alternative substrates, particularly epoxidases, is a fundamental aspect of the growing field of combinatorial biosynthesis. The specific alteration of these activities should constitute a further source of novel analogues. We investigated this possibility by directed inactivation of one of the P450s belonging to the biosynthetic gene cluster of an archetype polyene, pimaricin. RESULTS: A recombinant mutant of the pimaricin-producing actinomycete Streptomyces natalensis produced a novel pimaricin derivative, 4,5-deepoxypimaricin, as a major product. This biologically active product resulted from the phage-mediated targeted disruption of the gene pimD, which encodes the cytochrome P450 epoxidase that converts deepoxypimaricin into pimaricin. The 4,5-deepoxypimaricin has been identified by mass spectrometry and nuclear magnetic resonance following high-performance liquid chromatography purification. CONCLUSIONS: We have demonstrated that PimD is the epoxidase responsible for the conversion of 4,5-deepoxypimaricin to pimaricin in S. natalensis. The metabolite accumulated by the recombinant mutant, in which the epoxidase has been knocked out, constitutes the first designer polyene obtained by targeted manipulation of a polyene biosynthetic gene cluster. This novel epoxidase could prove to be valuable for the introduction of epoxy substituents into designer macrolides.

Antifungal Agents↗
PubMed1979

Effect of polyene antibiotics on the lectin-induced agglutination of transformed and untransformed cell lines.

Treatment of transformed Py3T3, SV101-3T3, and L1210 cells, as well as mitotic and Pronase-treated untransformed 3T3 cells, with the polyene antibiotics filipin, nystatin, and amphotericin B inhibited agglutination by wheat germ agglutinin. The effect of polyene antibiotic treatment was lectin and cell specific. Concanavalin A induced agglutination was not inhibited, wheat germ agglutination induced agglutination of untransformed 3T3 interphase cells was not influenced, and other aggregation phenomena, including those of erythrocytes with blood group specific antibodies or divalent cations, were unaffected by polyene treatments. This suggests that the formation of polyene-cholesterol complexes in transformed and erythrocyte cell membranes may specifically affect wheat germ agglutinin receptors and/or secondary events necessary for wheat germ agglutinin induced agglutination. Fluorescence studies of membrane filipin-cholesterol complexes showed that pretreating the cells with wheat germ agglutinin, but not concanavalin A, perturbed the fluorescence properties of filipin. Electron spin resonance studies with spin-labeled fatty acids revealed at best only a slight decrease in fatty acyl chain flexibility following filipin treatment. These studies indicate that there are not only quantitative differences between the agglutinability of transformed and untransformed cells with wheat germ agglutinin but that qualitative differences exist as well.

Agglutination↗
PubMed1979

Energy dependence and reversibility of membrane alterations induced by polyene macrolide antibiotics in Chlorella vulgaris.

The requirement of metabolic energy for the interaction of polyene macrolide antibiotics with eukaryotic organisms remains a controversial subject (for review see ref. 1) It has been claimed that the lethal binding of these antibiotics to the sterol target component of the hydrophobic core of the membrane, in accordance with the model of de Kruijff and Demel, is an energy-dependent process. When energy production is reduced by removal of all metabolisable substrates or by adding metabolic inhibitors, polyene binding and antifungal effects are also reduced. Metabolic energy may be required to maintain binding site accessibility or to move antibiotic molecules to the active site. The interaction is also restricted at low temperatures, possibly because of the reduced thermal mobilities of the groups concerned with antibiotic uptake. However, it should be emphasised that the interaction of polyene macrolides with artificial lipid membranes is a purely physicochemical process, although the type of permeability pathways induced are similar to those observed in natural membranes. Using Chlorella vulgaris as a model organism, we demonstrate here that the interaction of polyene macrolides with sensitive cells and the induction of lethal membrane permeability changes are energy-dependent processes or purely physicochemical phenomena, depending on the structure of the antibiotic used.

Anti-Bacterial Agents↗
PubMed1980

Charge-transfer complexes of some linear conjugated polyenes.

On adsorption of some electron-acceptor molecules on the solid films of all-trans-beta-carotene, beta-apo-8'-carotenal, astacene and methylbixin a new absorption band appears on the longer-wavelength side of the spectrum in addition to the original bands. The position of this new band is dependent on the electron affinity (EA) of the acceptor molecules, and the intensity of this band increases with the amount of adsorbed acceptor molecules. A linear relationship between the vmax. of the new band and EA was observed. The value of the ionization potential of the polyenes estimated from such linear relationship agrees satisfactorily with the value obtained by other methods. It has been concluded that the polyenes behave as electron donor and first form molecular charge-transfer complexes (of type [polyene . I2] with iodine) with electron acceptors, these finally dissociating to yield ionic complexes (of type [polyene . I+] with iodine).

Carotenoids↗
PubMed2006

Reduced susceptibility to polyenes associated with a missense mutation in the ERG6 gene in a clinical isolate of Candida glabrata with pseudohyphal growth.

Little information is available about the molecular mechanisms responsible for polyene resistance in pathogenic yeasts. A clinical isolate of Candida glabrata with a poor susceptibility to polyenes, as determined by disk diffusion method and confirmed by determination of MIC, was recovered from a patient treated with amphotericin B. Quantitative analysis of sterols revealed a lack of ergosterol and an accumulation of late sterol intermediates, suggesting a defect in the final steps of the ergosterol pathway. Sequencing of CgERG11, CgERG6, CgERG5, and CgERG4 genes revealed exclusively a unique missense mutation in CgERG6 leading to the substitution of a cysteine by a phenylalanine in the corresponding protein. In addition, real-time reverse transcription-PCR demonstrated an overexpression of genes encoding enzymes involved in late steps of the ergosterol pathway. Moreover, this isolate exhibited a pseudohyphal growth whatever the culture medium used, and ultrastructural changes of the cell wall of blastoconidia were seen consisting in a thinner inner layer. Cell wall alterations were also suggested by the higher susceptibility of growing cells to Calcofluor white. Additionally, complementation of this isolate with a wild-type copy of the CgERG6 gene restored susceptibility to polyenes and a classical morphology. Together, these results demonstrated that mutation in the CgERG6 gene may lead to a reduced susceptibility to polyenes and to a pseudohyphal growth due to the subsequent changes in sterol content of the plasma membrane.

Antifungal Agents↗
PubMed1977

Measurement of polyene antibiotic-mediated erythrocyte damage by release of hemoglobin and radioactive chromium.

Polyene antifungal antibiotics produce various degrees of membrane damage in sheep erythrocytes in vitro. Mediocidin, filipin, amphotericin B, and candicidin were found to result in greater damage than nystatin, pimaricin, and amphotericin B methyl ester. The degree of sensitivity of the cells varied by 100-fold for mediocidin verus amphotericin B methyl ester as measured by curves of hemoglobin release versus drug concentration. In erythrocytes prelabeled with radioactive chromium, release of the isotope through polyene-damaged cell membranes was found to occur at lower drug concentrations than measurable hemoglobin release, and the percentage of isotope released at the highest drug dose was consistently greater than the percentage of hemoglobin released. Thus, the isotope assay is a more sensitive indicator of polyene-induced membrane damage in the test system. These significant differences in release of molecules through polyene-induced membrane lesions indicate the complex nature of the binding and further interactions of this class of drugs with the plasma membrane.

Antifungal Agents↗
PubMed1979

Classification of polyene antibiotics according to chemical structure and biological effects.

Fourteen polyene antibiotics and six of their semisynthetic derivatives were compared for their effects on potassium (K(+)) leakage and lethality or hemolysis of either Saccharomyces cerevisiae or mouse erythrocytes. These polyene antibiotics fell into two groups. Group I antibiotics caused K(+) leakage and cell death or hemolysis at the same concentrations of added polyene. In this group fungistatic and fungicidal levels were indistinguishable. Group I drugs included one triene (trienin); tetraenes (pimaricin and etruscomycin); pentaenes (filipin and chainin); one hexaene (dermostatin); and one polyene antibiotic with unknown chemical structure (lymphosarcin). Group II antibiotics caused considerable K(+) leakage at low concentrations and cell death or hemolysis at high concentrations. The fungistatic levels were clearly separable from fungicidal. This group included the heptaenes (amphotericin B, candicidin, aureofungin A and B, hamycin A and B), and five of their semisynthetic derivatives (amphotericin B methyl ester, N-acetyl-amphotericin B, hamycin A and B methyl esters, and N-acetyl-candicidin). Nystatin, classified as a tetraene, and its derivative, N-acetyl nystatin, also were in this group.

Animals↗