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PubMedDate not supplied

Polyene resistance in ergosterol producing strains of Candida albicans.

Following nitrous acid mutagenesis, one nystatin- (nyl) and two amphotericin B (AB)-resistant (ab1 and ab2) mutants of Candida albicans were isolated and characterized. The three mutants plus a previously described cytochrome P450-deficient mutant (D10) of this organism were analyzed for polyene cross resistance. Cross resistance was noted for ny1 and D10 but not for ab1 and ab2. Sterol analysis indicated that ny1 was a delta 8-delta 7 isomerase mutant while ab1 and ab2 showed wild type sterol profiles. Fatty acid analysis showed no significant differences for ab1, ab2, and ny1 compared to wild type while D10 showed more pronounced differences. AB- and Triton X-100-induced potassium leakage studies indicated that ab1 and ab2 are resistant to low AB levels and ny1 is resistant to higher AB levels. In contrast, ab1 and ab2 were more resistant to detergent-induced potassium leakage than the wild type or mutants ny1 and D10. Significant differences in growth rate, ethanol sensitivity, and response to Tergitol were also noted among the resistant strains. The data indicate a different mechanism of action for the two polyenes and indicate a resistance mechanism for ab1 and ab2 based on subtle alterations of membrane structure rather than sterol substitution.

Amphotericin B↗
PubMedDate not supplied

Orointestinal yeast colonization of paediatric oncologic patients during antifungal prophylaxis: results of quantitative culture and Candida serology and comparison of three polyenes.

The orointestinal yeast colonization of 46 children with newly diagnosed malignancies was studied prospectively and longitudinally with quantitative cultures during remission induction chemotherapy. The initial colonization rate was 24%; only 28% of the patients remained free of yeasts during their entire treatment although all of them continuously received oral polyenes as antifungal prophylaxis. A randomized comparison of natamycin (suspension, lozenges), nystatin (suspension) and amphotericin B (suspension, lozenges) failed due to serious problems with patient compliance. Natamycin was best accepted by the patients and natamycin lozenges were the most efficacious drug in the oral cavity. The effectivity of the suspensions of nystatin and amphotericin B was similar; both were equally efficacious in the oral cavity and the gut. Assessment of faecal polyene concentrations by HPLC showed the highest results for amphotericin B (mean 6808 microgram(-1)). Regularly performed Candida serology (indirect haemagglutination, indirect immunofluorescence and immunodiffusion precipitation) revealed significant titre increases in 63% of the patients. In six cases, the synopsis of clinical picture, culture and serology strongly suggested systemic yeast invasion.

Adolescent↗
PubMed1993

Fluorescent polyene aliphatics as spectroscopic and mechanistic probes for bacterial luciferase: evidence against carbonyl product from aldehyde as the primary excited species.

The fluorescent alpha-parinaric acid (alpha-PAC) and beta-parinaric acid (beta-PAC) were converted to the corresponding aldehydes and alcohols all of which exhibited absorption and fluorescence properties closely resembling those of the parent acids. alpha-PAC and beta-PAC each binds to luciferase in competition with aldehyde. The hydrophobic nature of the aldehyde site was indicated by the enhanced fluorescence quantum yields of the bound alpha-PAC and beta-PAC. These two polyene acids and the beta-parinaryl alcohol were shown to stabilize the luciferase flavin-peroxide intermediate. alpha-Parinaraldehyde (alpha-PAD) and beta-parainaraldehyde (beta-PAD) were active substrates for Vibrio harveyi and Vibrio fischeri luciferases and, for the former enzyme, exhibited Km values similar to and quantum yields about 20-30% as those for decanal and dodecanal. For the V. harveyi luciferase with reduced FMN as a co-substrate, the alpha-PAD- or beta-PAD-initiated luminescence was indistinguishable from the normal emission obtained with octanal (lambda max 495 nm) showing no additional 430-nm component correlatable with emission from excited alpha-PAC or beta-PAC. In reactions using reduced 2-thioFMN for V. harveyi luciferase or reduced FMN for V. fischeri luciferase plus yellow fluorescent protein, the replacement of octanal by beta-PAD again resulted in no additional 430-nm emission. The lack of any emission correlatable with excited alpha-PAC, beta-PAC, or equivalent carbonyl product was not due to the quenching of the polyene moiety by chemical transformation, binding to luciferase, or a 100% energy transfer to the flavin 4a-hydroxide emitter.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehydes↗
PubMed1985

Activities of the modified polyene N-D-ornithyl amphotericin methyl ester and the azoles ICI 153066, Bay n 7133, and Bay l 9139 compared with those of amphotericin B and ketoconazole in the therapy of experimental blastomycosis.

We studied the efficacy of new experimental antifungal drugs, which represent molecular modifications of present active agents, in a murine model of blastomycosis. Ketoconazole, previously the best azole drug studied and which is protective when administered orally, was superior to a new oral imidazole, Bay l 9139, and a new oral triazole, Bay n 7133. A new oral triazole, ICI 153066, was markedly more effective than ketoconazole and is the only oral drug studied which came close to producing complete sterilization of all visceral infection in all animals treated. Amphotericin B, a polyene given parenterally, was shown to be more efficacious than any drug studied. It completely sterilized the infection. A modified polyene, N-D-ornithyl amphotericin methyl ester, was only slightly less effective on a milligram-per-kilogram basis.

Amphotericin B↗
PubMed1982

Effects of Polyenes, Detergents, and Other Potential Membrane Perturbants on an Osmotolerant Yeast, Saccharomyces rouxii.

The osmotolerance of Saccharomyces rouxii 48-28 was confirmed with both NaCl- and KCl-fortified growth media, with more tolerance being exhibited for the potassium salt. Washed and buffered cells from unfortified medium were challenged with a variety of compounds (and also with physical treatments) that potentially would elicit membrane perturbations. The efficacy of these brief treatments was judged primarily by monitoring subsequent viability. Change in the degree of expression of beta-fructofuranosidase (EC 3.2.1.26), which is cryptic in young cells of S. rouxii, was a second criterion. There was a linear correlation between cell death and enzyme expression for treatments with polyenes, detergents, some organic solvents which did not denature the enzyme, and various freeze-thaw regimens in graded amounts of glycerol. The species is relatively insensitive to polyene antimycotics, the order of decreasing effect being filipin, nystatin, and amphotericin B. S. rouxii was found to be less sensitive to osmotic shock than is Saccharomyces cerevisiae, but in neither species is beta-fructofuranosidase released to the medium. The sensitivity of S. rouxii to ionic detergents, but not to nonionic detergents, was rationalized as being due to cell wall discrimination against larger micelles for the nonionic examples. This was confirmed by showing that protoplasts were sensitive to both classes. In cultures older than 5 days the normal agreement between colony-forming units and methylene blue exclusion (another test of viability) no longer held. Delayed fermentation of sucrose by S. rouxii, which is a diagnostic feature of the species, is explained by death of some cells, expression of their beta-fructofuranosidase, and utilization of the monosaccharides by the surviving cells.

Journal Article↗
PubMed1982

A comparison of the effects of several antifungal imidazole derivatives and polyenes on Candida albicans: an ultrastructural study by scanning electron microscopy.

The early events in the interaction of two polyene (amphotericin B and nystatin) and five imidazole (clotrimazole, ketoconazole, miconazole, isoconazole, and econazole) antimycotics used at fungicidal concentrations with the surface of Candida albicans were studied by scanning electron microscopic examination of treated intact young yeast cells, treated spheroplasts, and spheroplasts liberated from treated young yeast cells. In all cases, treatment lasted 2 h. The polyenes passed through the yeast cell wall and interacted with the cytoplasmic membrane causing the spheroplasts to lose their characteristic spheric form and to liberate their contents. Clotrimazole caused the formation of numerous circular openings in the cytoplasmic membrane, but only when the agent was used to treat spheroplasts directly. Ketoconazole, miconazole, isoconazole, and econazole interacted with the cell wall causing formation of convolutions and wrinkles. The three imidazole derivatives that are structurally closely related, miconazole, isoconazole, and econazole, inhibited the enzyme-catalyzed release of spheroplasts from young yeast cells.

Amphotericin B↗
PubMed1978

Investigation of polyene macrolide antibiotic-induced permeability changes in vesicles by 31P nuclear magnetic resonance.

The permeability of egg yolk lecithin (EYL) vesicles to Pr3+ has been measured by 31P nuclear magnetic resonance (nmr) spectroscopy. Measurable Pr3+ leakage into the internal aqueous compartment of EYL vesicles at ambient (21 degrees C) temperature required the presence of small (7--10 mol%) amounts of dicetyl phosphate (DCP). The permeability of DCP-containing vesicles is decreased by incorporation of sterol (cholesterol greater than ergosterol approximately 5.6-dihydroergosterol greater than zymosterol) into the lipid bilayer. Addition of the polyene macrolide antibiotic, nystatin, to DCP-containing EYL vesicles with and without sterol resulted in increased Pr3+ permeability at the three temperatures studied (21--37.5 degrees C). Permeability changes observed upon addition of nystatin to sterol-impregnated, DCP-containing vesicles varied with sterol structure: ergosterol approximately 5,6-dihydroergosterol greater than cholesterol approximately zymosterol. These results are compared with other polyene macrolide induced permeability changes on model and natural membrane systems. Permeability changes induced by nystatin in sterol-free EYL vesicles were generally greater than for comparable sterol-containing vesicles. This is attributed to a nonspecific interaction of the antibiotic with the latter vesicles.

Cell Membrane Permeability↗
PubMed1980

Pathophysiology of long-chain polyene fatty acids in heart muscle.

The polyene fatty acid composition of cardiac phospholipids is modified by age, diet and stress in the rat. In the aging heart there is a progressive replacement of 18:2n6 by 20:4n6 in phosphatidylcholine (PC) and a replacement of 18:2n6 by 22:6n3 in phosphatidylethanolamine (PE). Norepinephrine stress accelerates aging of cardiac PC and PE. Dietary fish oil causes a replacement of 18:2n6 and 20:4n6 by 22:6n3 in cardiac PC and PE but not in cardiolipin. Studies on human cardiac autopsy samples suggest that: (a) polyene fatty acid composition changes with age; (b) stability of cardiac phospholipids is a function of the fatty acid composition, chain length and unsaturation; (c) coronary atherosclerosis is associated with a reduced content of 18:2n6 in phospholipids, an increased content of glycerides of abnormal composition and an unexpectedly low level of free fatty acids (FFA) in the heart muscle, and (d) many cases of sudden cardiac death in the absence of marked coronary artery stenosis or myocardial infarction may be associated with significant alterations in myocardial levels of FFA (increase) or PE (decrease).

Aging↗
PubMed1990

YS-822A, a new polyene macrolide antibiotic. I. Production, isolation, characterization and biological properties.

A new polyene macrolide antibiotic, YS-822A was isolated from the culture filtrate of a mutant strain H-8 of Streptoverticillium eurocidicum var. asterocidicus S-822. Whereas the original S-822 strain produced not only YS-822 substances but also teleocidin as by-product which is well-known as a strong carcinogenic promoter, the mutagenized H-8 strain produced the antibiotic with only a trace amount of teleocidin. Chemical and biological characterizations of the antibiotic revealed that YS-822A (molecular formula: C37H59NO14) is a new polyene macrolide with a wide antifungal spectrum and a low acute toxicity.

Animals↗
PubMed1991

YS-822A, a new polyene macrolide antibiotic. II. Planar structure of YS-822A.

The planar structure of a new polyene macrolide antibiotic, YS-822A, which was isolated from the culture filtrate of a mutant strain H-8 of Streptoverticillium eurocidicum var. asterocidicus S-822, was established as I on the basis of spectroscopic evidences and by comparison spectroscopic data with nystatin A1 (II) and amphotericin A (III), representative polyene macrolide antibiotics. Molecular formula of YS-822A was established as C37H59NO14 (MW 741) by elemental analysis, NMR, and FAB mass spectra. The UV spectrum of YS-822A was very similar to that of nystatin A1, suggesting that YS-822A also has a conjugated all-trans-tetraene moiety. 1H and 13C NMR spectra of YS-822A showed a number of broad and overlapped signals, but the 1H-1H and 13C-1H COSY spectra implied the existence of a mycosamine moiety and several other partial structures. The connectivity of these partial structures was established by extensive 2D NMR experiments, including homonuclear Hartmann-Hahn and heteronuclear multiple-bond connectivity measurements, which led to the determination of the gross planar structure of YS-822A as I.

Amphotericin B↗
PubMed1976

[The change of template activity of dog kidney chromtin by polyene antibiotics in vivo and in vitro].

Effect of amphotericin B and nistatin on template activity of nuclear membrane-bound (DNPm) and free (DNPo) dog kidney chromatin after intravenous injections of antibiotics and after the incubation of isolated kidney cell nuclei with the antibiotics is studied. It is found that injections of amphotericin B and nistatin resulted in the increase of DNPo template activity in RNA polymerase system, the stimulating effect of nistatin being higher than that of amphotericin B. Injections of nistatine stimulated also template activity of DNPm, while amphotericin B produced no effect on DNPm. When studing the effect of polyene antibiotics on template activity of DNPo and DNPm in vitro, it is found that the intensity of RNA synthesis after incubation of isolated nuclei with antibiotics is considerably increased, and stimulating effect of nistatin is higher than of amphotericin B. Both antibiotics produced no effect on template activity of DNP in vitro. Thus, comparative analysis of changes in template activity of dog kidney chromatin under the effect of polyene antibiotics in vivo and in vitro has revealed the similarity of these drugs and draws to the conclusion that nistatin and amphotericin B produce a direct effect on template activity of chromatin.

Amphotericin B↗
PubMed1992

Absorption and fluorescence spectra of polyene antibiotics in the presence of cholesterol.

The alterations in the absorption and fluorescence spectra observed for the polyene antibiotics filipin and nystatin in the presence of cholesterol are due to an exciton interaction (polyene aggregates) and cannot be attributed to a specific sterol-antibiotic complex. Filipin and nystatin molecules partition into the sterol aggregates, these structures being very efficient to induce exciton interaction; the observed splitting profile indicates that the chromophores are in a stacked arrangement (parallel transition dipoles). For filipin incorporated in lipid bilayers, the sterol is able to induce the same type of aggregate, at variance with nystatin.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1990

Inhibition of erythrocyte ghost ATPase by polyene antibiotics.

The effect of micromolar concentrations of polyene antibiotics on erythrocyte ghost ATPase activities has been studied. (Mg2+)-ATPase is inhibited by amphotericin B and amphotericin B methyl ester, whereas (Na+ + K+ + Mg2+)-ATPase is inhibited by amphotericin B and lucensomycin. (Ca2+ + Mg2+)-ATPase is only slightly affected by polyene antibiotics.

Amphotericin B↗
PubMed1987

[Spectrophotometric research on the photochemical isomerization of the polyene macrolide antibiotic levorin A2].

Photochemical (cis-trans) isomerization of levorin A2 under the effect of light at wave lengths of 313 and 365 nm (excitation of the polyenic system and p-aminobenzoylene respectively) was studied. In case of the polyenic system excitation the reaction was reversible and the process quantum yield was extremely low while the use of light at the wave length of 313 nm as photochemical activator resulted in increasing the quantum yield by two orders. In this case triplet-triplet transfer of energy took place. A calculation procedure is recommended for quantitative determination of the quantum yield of levorin isomerization including direct and reverse reactions. The procedure may be used in study of other objects with similar mechanisms of phototransformation.

Antifungal Agents↗
PubMed1965

Candicidin and other polyenic antifungal antibiotics.

About 50 polyenic antifungal antibiotics produced by actinomycetes have been isolated and described. Among these are the most effective antimonilial agents so far known. These polyenes can be classified into four broad groups depending on the number of conjugated carbon-to-carbon double bonds that are present in their chromophores. Only some of the tetraenes (four conjugated double bonds), such as nystatin and pimaricin, and a few heptaenes (seven conjugated double bonds), such as amphotericin B, Trichomycin candicidin and hamycin, have found practical application in the treatment of infectious diseases caused by fungi. Nystatin and pimaricin show the least in vitro activity against fungi, while trichomycin and candicidin are the most active. Recent clinical investigations carried out in the USA have shown that candicidin is very effective in the treatment of vaginal monilial infections.

Antifungal Agents↗
PubMed1984

[Sensitivity of Candida strains to polyenic antibiotics in the treatment of oral candidiasis].

Sensitivity of 146 clinical strains of Candida albicans to nystatin, levorin and amphoglucamine was studied on solid media with the replica method. The strains were isolated from 79 patients with candidiasis of the oral mucosa. It was found that sensitivity of the fungi to the polyenic antibiotics was different which should be considered in treatment of candidiasis. On the basis of the mean MICs for the clinical strains and their distribution by the MICs it was shown that the activity level of levorin and amphoglucamine was higher than that of nystatin. During the treatment resistance of the Candida strains to the polyenic antibiotics increased and cross resistance developed which required application of other treatment means.

Amphotericin B↗
PubMed1984

[Effects of a basic metabolic diet rich in polyene fatty acids on the pattern of glycerophospholipid fatty acids in patients with hyperlipoproteinemia].

In 77 patients with primary hyperlipoproteinaemia of the types IIa, IIb and IV who for 8 months had been treated with a metabolic basic diet enriched by polyene fatty acid gas-chromatographic analyses of the fatty acid compound of the glycerophospholipids were carried out in four-month intervals. In all three types of hyperlipoproteinaemia in a different size and increase of poly-unsaturated and a decrease of saturated and mono-unsaturated fatty acid could be observed. A metabolic basic diet rich in polyene fatty acid has a favourable influence on atherogenic constellations of the fatty acids of the glycerophospholipids.

Fatty Acids, Unsaturated↗
PubMed1976

[Effect of polyene antibiotics on protein synthesis by free and membrane-bound ribosomes of Candida albicans].

Polyene antibiotics (levorin, nistatin, amphotericin B) inhibit protein synthesis at concentrations decreasing 14C-amino acid incorporation into Candida albicans protoplasts by 30--60%, the depression of membrane permeability beginning earlier than protein synthesis inhibition. Fractionation of protoplast lysates revealed that protein synthesis by free ribosomes was inhibited by antibiotics stronger than in case of membrane-bound ribosomes. It is supposed that different response of two ribosome classes for polyenes-induced damages is due to different sensitivity of free and membrane-bound ribosomes to the decrease of intracellular K+ concentration.

Amphotericin B↗