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PubMed1973

Selective membrane toxicity of the polyene antibiotics: studies on natural membranes.

The effect of polyene antibiotics on Candida albicans, human erythrocytes, and Acholeplasma laidlawii was studied. The results sustain the observations made with lecithin-sterol liposomes. The distribution of double bonds in the membrane sterol nucleus appears to be of major importance in conferring polyene susceptibility; those sterols with the ergosterol nucleus are far more effective than those with a nucleus similar to cholesterol. Different polyenes vary in their membrane selectivity. The clinical implications of these observations are discussed.

Acholeplasma laidlawii↗

PubMed2004

Chemical diversity of polyene macrolides produced by Streptomyces noursei ATCC 11455 and recombinant strain ERD44 with genetically altered polyketide synthase NysC.

The gram-positive bacterium Streptomyces noursei ATCC 11455 produces a complex mixture of polyene macrolides generally termed nystatins. Although the structures for nystatins A(1) and A(3) have been reported, the identities of other components of the nystatin complex remain obscure. Analyses of the culture extract from the S. noursei wild type revealed the presence of several nystatin-related compounds for which chemical structures could be suggested on the basis of their molecular weights, their UV spectra, and knowledge of the nystatin biosynthetic pathway. Nuclear magnetic resonance (NMR) studies with one of these polyene macrolides identified it as a nystatin analogue containing a mycarose moiety at C-35. A similar investigation was performed with the culture extract of the ERD44 mutant, which has a genetically altered polyketide synthase (PKS) NysC and which was previously shown to produce a heptaene nystatin analogue. The latter compound, tentatively named S44HP, and its derivative, which contains two deoxysugar moieties, were purified; and their structures were confirmed by NMR analysis. Nystatin analogues with an expanded macrolactone ring were also observed in the extract of the ERD44 mutant, suggesting that the altered PKS can "stutter" during the polyketide chain assembly. These data provide new insights into the biosynthesis of polyene macrolide antibiotics and the functionalities of PKSs and post-PKS modification enzymes.

Anti-Bacterial Agents↗

PubMed1975

Sequence of biosynthesis of the components of the polyene macrolides candidin and candihexin: macrolide aglycones as intracellular components.

A sequential formation of the single components of the polyene macrolide candidin complex (heptaene) has been found. In addition to the three components occurring in the candidin complex at the end of the fermentation, two other "early" all-trans heptaene components have been characterized. They exist only during the phase of active biosynthesis of candidin. Two of the components of the polyene macrolide candihexin complex (hexaene) that have been described as lacking amino sugar were the only intracellular (mycelium-associated) components observed under conditions in which no extracellular polyene remained attached to the producing cell. The results indicate that glycosylation of the macrolide ring takes place during the secretion process.

Antifungal Agents↗

PubMed1965

DEVELOPMENT OF RESISTANCE TO POLYENE ANTIBIOTICS IN CANDIDA ALBICANS.

Hebeka, Elias K. (Rutgers, The State University, New Brunswick, N.J.), and Morris Solotorovsky. Development of resistance to polyene antibiotics in Candida albicans. J. Bacteriol. 89:1533-1539. 1965.-Strains of Candida albicans resistant to the polyenes candidin and amphotericin B, but not to nystatin, were developed by sub-culturing the organism in gradually increasing concentrations of the antibiotic in broth on a shaker, or by repeated transfer on gradient plates. Demonstration of resistance on solid media was best observed when a purified agar, Ionagar no. 2 (Oxoid), was used in preparing the medium. Strains that were 150-fold resistant to candidin, and 4-, 16-, 45-, and 60-fold resistant to amphotericin B were developed. The degree of resistance depended on the strain, the type of medium, and, most importantly, on the antibiotic used. The polyenes candidin, amphotericin B, nystatin, and fungimycin and the nonpolyenes griseofulvin and eulicin were used to extend the scope of study of cross-resistance. Cells rendered resistant to candidin were also resistant to amphotericin B, but not to nystatin, fungimycin, or griseofulvin. Cells rendered resistant to amphotericin B showed cross-resistance to candidin, but not to nystatin, fungimycin, or griseofulvin. Candidinor amphotericin B-resistant strains were more sensitive to eulicin than their parent strains. Increased resistance to candidin or amphotericin B was accompanied by a decrease in virulence for mice, the rate of growth, the ability to reduce bismuth sulfite, and by an increased tendency for filamentation. No change in the ability to form chlamydospores was noticed.

Amphotericin B↗

PubMedDate not supplied

Exposure to subtherapeutic concentrations of polyene antifungals suppresses the adherence of Candida species to denture acrylic.

BACKGROUND: The adherence of Candida species to denture acrylic is the initial event leading to Candida-associated denture stomatitis, with Candida albicans being the main aetiological agent. However, the increased incidence of immunocompromised patients in the community has resulted in the emergence of a number of non-albicans Candida species as causative agents of this disease, which is commonly managed by topically delivered polyene antifungals. Hence, we investigated the effect of the exposure of denture acrylic surfaces to nystatin and amphotericin B on the subsequent adhesion of six different Candida species. METHODS: Acrylic strips were exposed to subtherapeutic concentrations of the two polyenes for 30 min, and the adhesion of 4 isolates each of C. albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis and Candida tropicalis was assessed using a previously described in vitro method with slight modifications. RESULTS: Overall, the results indicated a 35.9% (p < 0.01) and 63.1% (p < 0. 01) reduction, respectively, in yeast adhesion to denture acrylic following exposure to nystatin and amphotericin B, although this effect was not uniform for all the tested isolates. Thus, all C. glabrata, 3 C. guilliermondii and a single isolate each of C. krusei, C. parapsilosis and C. tropicalis were not significantly affected by nystatin exposure, and a single isolate each of C. glabrata and C. guilliermondii were not significantly affected by amphotericin B. CONCLUSIONS: The present data, the first on the effect of polyenes on a wide range of Candida species, indicate that the in vitro exposure of denture acrylic to subtherapeutic concentrations of nystatin and amphotericin B suppresses the adherence of pathogenic Candida species in general.

Acrylic Resins↗

PubMed1976

Effects of polyene macrolide antibiotics on normal and protoplast type L-form cells of Escherichia coli W1655F+.

The action of the polyene macrolide antibiotics mycotrienin, pimaricin, lucensomycin, tetramycin, rimocidin, nystatin, filipin, lagosin, pentaene antibiotic 2814P, flavomycoin, flavofungin, hexaene antibiotic 5001P, and candicidin, including perhydro derivatives of them, on wall-less stable protoplast type L-form and normal rod form cells of E. coli W1655F+ was studied. No inhibition of the normal rod form cells was detected. In contrast to these results the growth of the L-form cells was inhibited by all of the substances tested, with the exception of pimaricin. Further experiments have shown that the differences in sensitivity of normal and L-form cells cannot be explained by differences in sterol content, the target site of polyene antibiotics in sensitive eukaryotic cells. According to our results it is obvious that the cell wall of the normal cells functions as a penetration barrier to polyene antibiotics.

Anti-Bacterial Agents↗

PubMed1975

[Effect of gamma-irradiation on some biological and physico-chemical properties of polyene antibiotics].

Deep effect of gamma-rays on polyenic antibiotics was studied. It was shown that gamma-radiation induced radiation-chemical oxidation of the substances. The chromatographic analysis showed that the levorin degradation products were identical to the polyenic products of the antibiotic oxidative destruction. As for mycoheptin and amphotericin B, destruction of their molecules to non-polyenic products was observed. It was found that toxicity of the levorin aromatic heptaen did not practically change after gamma-irradiation in high doses. The toxicity of mycoheptin and amphotericin B, non-aromatic heptaens increased after exposure to high doses of gamma-rays.

Amphotericin B↗

PubMed1985

[Anti-amebic effect of polyenic antibiotics].

All-Union Research technological Institute of Antibiotics and Medical Enzymes, Leningrad. Institute of Epidemiology, Virology and medical parasitology, Ministry of Health of the Armenian SSR. The effect of polyenic antibiotics made in the USSR on development of E. histolytica and E. moshkovski was studied. The following antibiotics were used: levorin and its derivatives, mycoheptin, amphotericin B, amphoglucamine and nystatin. The antibiotics were compared with emetine and metronidazole. Some drugs of the imidazole group were also included into the study. On the whole 15 drugs were tested for their antiamebic activity. All the polyenic antibiotics showed a high antiamebic activity. Levorin and its derivatives were the most active. Their MICs ranged from 0.1 to 5.38 micrograms/ml. The most active of the new imidazoles was 100 times less effective than sodium levorin. The studies show that the polyenic antibiotics have an antiamebic activity and a broad antiprotozoal spectrum.

Amebicides↗

PubMed1987

[Sensitivity of dimorphic Candida albicans cells to polyene antibiotics and their combinations with other biologically active substances].

It was shown that polyenic antibiotics and their combinations with some other antifungal and antibacterial agents prevented transformation of the C. albicans yeast phase into the tissue one. Moreover, the fungus tissue form proved to be more sensitive than the yeast form to the drugs and especially to their combinations. The in vitro findings were confirmed by the in vivo studies. Combinations of amphotericin B with methacycline, rifampicin, 5-fluorocytosine or polymyxin B were more efficient than the polyene alone. Summation of the drug antifungal effects provided a 4-fold decrease in the polyene quantity required for administration to experimental animals.

Antifungal Agents↗

PubMed1981

[Role of sterols in the interaction of polyene antibiotics with lipid membranes].

The problem whether the membrane sterols are indirect acceptors of polyenic antibiotics or they play the role of substances providing conditions (at the expense of putting in order the membrane phospholipids) for formation of conductive complexes (ionic canals) from the antibiotic molecules is discussed. The comparative study on the ability of sterols of various structure (ergosterol, 7-dehydrocholesterol, cholesterol, 5 alpha-cholestan-3 beta-ol) to interact with the membrane phospholipids and to increase the sensitivity of such membranes to amphotericin B showed no correlation between the levels of these properties. The value of the changes in the cross elasticity module (E) of artificial bilayer lipid membranes from egg lecithin on introduction of the above sterols into their composition was used as the criterion for the interaction level. The absence of correlation between the above properties of the sterols indicated that the role of the sterols in interaction of polyenic antibiotics with the membranes could not be considered as the only effect of the sterols on putting in order the phospholipids, which confirmed the hypothesis on the acceptor function of the sterols with respect to polyenic antibiotics. The study of the effect of amphotericin B on the elastic properties of the cholesterol-containing bilayer membranes isolated from egg lecithin showed tha the values of the longitudinal and cross elasticity modules of the membranes did not change during introduction into the membranes of the ionic canals.

Amphotericin B↗

PubMed1980

[Effect of polyene antibiotics on the increase in specific resistance due to inactivated antiviral vaccines].

The capacity of polyenic antibiotics, such as water soluble forms of amphotericin B, mycoheptin, nystatin and levorin to stimulate immunogenicity and interferonogenic activity of inactivated antiviral vaccines was shown. The protective effect of the vaccine against rabies or forest-spring encephalitis in albino mice was more pronounced on its two-fold use in combination with the antibiotic than that on its use alone. The most significant results were obtained with highly diluted vaccines supplemented with amphotericin B. In this case the resistance index was 2 times higher than on vaccination without amphotericin B. In comparative assays of 4 various lots of vaccines against rabies the ED50 of every inactivated vaccine corresponded to thrice as low levels of the antirabies antigen than on vaccination without the polyen. The problems of the mode of action of the polyenic antibiotics and antiviral inactivated vaccines used in combination are discussed.

Animals↗

PubMedDate not supplied

[The effect of lovastatin on sterol synthesis and yeast resistance to polyene antibiotics].

Lovastatin (monocolin K) is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA-reductase. Its influence on the growth of a lovastatin sensitive strain of Rhodotorula rubra, the biosynthesis of ergosterol and the resistance to polyenic antibiotics was studied. It was shown that the lovastatin action on the strain depended on the inhibitor dose. In a concentration of 0.1 to 0.5 micrograms/ml lovastatin inhibited the yeast growth and ergosterol biosynthesis. Higher concentrations of the inhibitor in the medium led to the recovery of the sterol biosynthesis. It was also demonstrated that a decrease of the ergosterol level in the cells under the influence of lovastatin resulted in the development of resistance in the yeast to polyenic antibiotics such as nistatin and amphotericin B. Correlation between the ergosterol level in the yeast cells and their susceptibility to the polyenic antibiotics was observed.

Anti-Bacterial Agents↗

PubMed1993

[The cellular acid phosphatase activity in yeast-like fungi of the genus Candida exposed to ultrasound, polyene antibiotics and dyes].

The activity of one of the lysosomal membrane marker enzymes--acid phosphatase from the Candida yeast fungi on their exposure to ultrasound (US), polyenic antibiotics (amphotericin B and nystatin) dye antiseptics (ethacridine lactate, methylene blue), and their combinations was assayed. The impact of US and the drugs, in particular their combination, was found to be followed by activation of the fungal lysosomal apparatus function and increases in their catabolic processes. The highest rise in lysosomal catabolic activity was found when the polyenic antibiotics were used in combination with US, which reflects the higher damaging effect of this combination against Candida lysosomal membranes than the dyes and of these antibiotics and US alone. The studies provide strong evidence for the preference of the combined use of US and the polyenic antibiotics in candidiasis as a factor enhancing their fungicidal effect against Candida yeast fungi.

Acid Phosphatase↗

PubMed1977

[Method of the spectrophotometric analysis of polyene antibiotics].

The method of quantitative spectrophotometric analysis of several substances in the presence of admixtures is described. The method is based on presentation of an unknown spectrum of the admixture absorption by the polyen of the 3rd or 4th power depending on the wave length. The optical density of the mixture of any wave length is expressed by the linear equation, including the Firord equation for the known components and the given polynome. The system of such equations for 10-15 analytical wave lengths may be solved with the method of the least squares using an electronic computer. The system solvations are the concentrations of the mixture components to be determined and the polynome coefficients. The method was tested on model mixtures composed of amphotercin B, myocheptin, nystatin and griseofulvin, as well as of isomeric nitroanilines playing the role of the admixture. The analysis error for the compounds of the polyenic structure having not less than 2 absorption maxima in the given spectral ranges did not exceed 1-3 per cent. As for the compounds with a single maximum or when the admixture included also polyenic compounds the analysis error increased up to 6--50 per cent.

Amphotericin B↗

PubMed2005

Electronic energy levels in all-trans long linear polyenes: the case of the 3,20-di(tert-butyl)-2,2,21,21-tetramethyl-all-trans-3,5,7,9,11,13,15,17,19-docosanonaen (ttbp9) conforming to Kasha's rule.

The absorption, fluorescence and fluorescence excitation spectra for 3,20-di(tert-butyl)-2,2,21,21-tetramethyl-all-trans-3,5,7,9,11,13,15,17,19-docosanonaen (ttbP9) in dilute solutions of 2-methylbutane were recorded at temperatures over the range 120-280 K. The high photostability of this nonaene allows us to assert that it exhibits a single fluorescence and that this can be unequivocally assigned to emission from its 1(1)B(u) excited state, it being the first excited electronic state. Available photophysical data for this polyene and the wealth of information reported for shorter all-trans polyenes allow us to conclude that if the first excited electronic state for the chromophore possessed 2(1)A(g) symmetry, then the energy of such a state might have been so close to that of the 1(1)B(u) state that: 1) the radiationless internal conversion mechanism would preclude the observation of the emission from the 1(1)B(u) state reported in this work and 2) the 2(1)A(g) state reached through internal conversion would be vibrationally coupled to 1(1)B(u) and would facilitate the detection of the emission from 2(1)A(g), which was not observed in any of the solvents used in this work. The spectroscopic and photochemical implications of these findings for other polyenes are discussed.

Journal Article↗

PubMed1989

Relationship between ionophoric and haemolytic activities of perimycin A and vacidin A, two polyene macrolide antifungal antibiotics.

The ionophoric and hemolytic activities of two antifungal aromatic heptaenes: vacidin A and perimycin A, were studied on human red blood cells. Measurements of hemolysis, K+ influx and efflux, H+ movement and potential difference across the cell membrane, show that the hemolytic activity, being related to the K+ permeability induced by the polyene, is strongly dependent on the ability of this polyene to induce H+ movement. It was shown that: (1) both antibiotics have approximately the same efficiency in inducing K+ permeability, but a 100-fold difference in their hemolytic activity; (2) their hemolytic activity is related to their ability to induce H+ movement; (3) the protonophoric activity requires the existence of a free carboxyl group in the macrolide ring, as in vacidin A. The hemolytic activity is determined by the intrinsic efficiency of a K+/H+ exchange induced by this polyene. With perimycin A, which lacks the free carboxyl group, the hemolytic activity is dependent on the Cl- conductive flux which slows down the K+ flux.

Acetophenones↗

PubMed1990

Use of a cloned gene involved in candicidin production to discover new polyene producer Streptomyces strains.

A p-aminobenzoic synthase gene (pabS) from Streptomyces griseus IMRU 3570 involved in candicidin production was used as probe to find new aromatic polyene producing Streptomyces strains. The pab gene hybridizes with 6 out of 16 Streptomyces strains, and those strains which hybridize turned out to be polyene producers. Such strains were never before described as polyene producers.

Anti-Bacterial Agents↗

PubMed2004

Membrane-permeabilizing activities of amphidinol 3, polyene-polyhydroxy antifungal from a marine dinoflagellate.

Amphidinols, which are polyene-polyhydroxy metabolites produced by the marine dinoflagellate Amphidinium klebsii, possess potent antifungal and hemolytic activities. The membrane permeabilizing actions of amphidinol 3, the most potent homologue, were compared with those of polyene antibiotics, amphotericin B (AmB) and filipin, in hemolytic tests, 23Na nuclear magnetic resonance (NMR)-based membrane permeabilizing assays, and UV spectroscopy for liposome-bound forms. In Na+ flux experiments using large unilamellar vesicles (LUVs), ion efflux by amphidinol 3 was inhibited by cholesterol or ergosterol, which was opposed to previous results [J. Mar. Biotechnol., 5 (1997) 124]. When the effect of the agents on the size of vesicles was examined by light scattering experiments, amphidinol 3 did not significantly alter their size while filipin and synthetic detergent Triton X-100 did. The observations implied that the activity of amphidinol 3 was mainly due to formation of large pores/lesions in liposomes rather than detergent-like disruption of membrane. The pore/lesion size was estimated to be 2.0-2.9 nm in diameter on the basis of osmotic protection experiments using blood cells. The UV spectra in liposomes, which revealed the close interaction of polyene moieties in a lipid bilayer, further implied that the membrane activity of amphidinol 3 is caused by the molecular assemblage formed in biomembrane. These results disclose that amphidinol 3 is one of few non-ionic compounds that possess potent membrane permeabilizing activity with non-detergent mechanism.

Alkenes↗