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PubMed1983

A new polyene with antimycotic activity produced by a streptomycete from the rhizosphere of an indoor plant.

From the rhizosphere of a potted Sanseviera trifasciata, a Streptomyces griseus strain with a broad antifungal activity was isolated; in the soil of this plant, a sole hyphomycete, Aspergillus niger, was found in pure culture at 37 degrees C. This streptomycete produced a polyene, belonging to the pentaene group. It was found to inhibit, in vitro, the growth of all the 123 strains tested; the strains belonging to the genera Aspergillus, Cryptococcus, Candida, Trichophyton, Epidermophyton, Microsporum, Penicillium and Mucor. An antimycotic activity of this substance was also found to be present after i.v. administration to white mice infected with Cr. neoformans. Toxicological tests will have to show if this polyene could be considered as a candidate antimycotic drug. The soil of potted indoor plants is discussed as a possible habitat for streptomycetes with defined antifungal activities.

Animals↗

PubMed1980

[The influence of so-called "diet" fats high in polyene acids on blood constituents, serum cholesterol and organ systems].

The Effect of Various Alimentary Fats, Especially "Diet" Fats With High Proportions of Polyene Acids on the Blood Count, Cholesterol Levels and Organ Systems: This paper describes our observations on the possible toxicity of highly unsaturated fatty acids on the cell systems of the red blood, the liver and kidney. At the same time the necessity of maintaining a normal level of cholesterol in the blood and a stable pool of saturated fatty acids in the serum is pointed out with reference to our own investigations. By means of a reference record histogram, the lower critical point of cholesterol level is verified. A correlation between the low cholesterol level, relatively low hemoglobin values and low erythrocyte count is substantiated., By means of a nutritional physiology study in patients with defined anemias and cholesterol deficit, an attempt was made to establish a causal connection between low cholesterol and anemia. Further, it could be shown that highly unsaturated fatty acids (polyene acids) of the C189:2 cis ("curved fats") type such as occur in diet margarines, thistle oil and other vegetable oils in high concentrations, can cause damage to cell membranes and the cell systems of the red blood, the liver and kidney by excessive ingestion in the food. Biochemical work on the present knowledge of the formation of lipofuscin (the "age pigment") by polymerization products from unsaturated fatty acids is referred to. In a controlled nutritional physiology trial in pigs the facts observed in human medicine were confirmed. So it is postulated that the curative pronouncements claimed by the bottlers of thistle oil and the manufactures of diet margarines are not valid. Taking the Codex Alimentarius of the FAO/WHO, which gives the acceptable daily dosage in mg/kg body weight as a guide, according to the present state of toxicological information, a maximum of 10 g unsaturated fatty acids of the C18:2 cis type can be consumed for a lifetime without suffering noticeable harm. This corresponds to a highly unsaturated fatty acids proportion of less than 8% in the daily diet.

Anemia↗

PubMed1975

[Ionization of the acid-base groups of polyene antibiotics in aqueous solutions].

The acid-base characteristics of polyenic antibiotics, such as nystatin, mycoheptin and levorin in aqueous solutions were studied. A special procedure provided the use of potentiometric titration for investigation of ionization of the groups of vater-insoluble substances. The ionization constants of the carboxylic and amine groups of the antibiotics at several temperatures were determined. It was found that ionization of the acid group did not practically depend on the temperature. At the same time the heat effect of the amine group ionization was significant and amounted to about 10 kcal/mole. Thermodynamic analysis of the ionization process of the polyenic antibiotics in aqueous solutions was performed. Integral components defining the process energetics were calculated.

Acid-Base Equilibrium↗

PubMed1981

[Mathematical model of zone formation taking into account the inactivation of polyene antibiotics diffusing into an inoculated gel].

The procedure for investigation of the inhibition growth zone formation on diffusion of polyenic antibiotics into inoculated gel is presented. The model of strong inactivation is applicable when the drug inactivation is significant during the period of the zone formation and not only during the period of the 2-fold increasing of the number of the test microbe cells. The experimental study on the passive inactivation of polyenic antibiotics, such as levorin, amphotericin B, mycoheptin and nystatin showed that during the period of the zone formation the first 2 antibiotics were inactivated to such a level that their passive inactivation could be considered strong. A case of drug active inactivation with the test microbe cells is discussed. An equation for the specific period of the zone formation with respect to this particular case of the drug strong inactivation was developed. The parameters of the active inactivation were estimated. The results for levorin are in good agreement with some of its physico-chemical properties, i. e. poor solubility and mycella formation.

Anti-Bacterial Agents↗

PubMed1993

[High performance liquid chromatography in studies of component composition of polyene macrolides].

The published data on the use of HPLC in studies on the chemistry of polyene macrolide antibiotics are summarized and the conditions for HPLC, the use of various sorbents, the impact of the ratio of the organic solvents and buffer solutions, etc. are discussed comparatively. Several aspects of the use of HPLC are indicated i.e. the identification of polyene antibiotics (heptaenes, pentaenes and hexaenes), the standardization and investigation of the antibiotic homogeneity and quality, the purification of the antibiotics and the determination of the amphotericin B content in tissues and plasma.

Anti-Bacterial Agents↗

PubMed1978

Differential control of synergistic effect with polyene macrolide antibiotics upon Chinese hamster cells in vitro.

An amphotericin B-resistant cell (AMBR-1), which was isolated from aneuploid Chinese hamster cells (V79), was found to show much higher resistance than the parent V79 cells to other polyene antibiotics, such as pentamycin and filipin. To obtain the 50 to 60% inhibition of the control protein synthesis activity by a synergistic combination of fusidic acid and amphotericin B, 50 microgram fusidic acid per ml were combined with 10 microgram amphotericin B in V79 cells, whereas in AMBR cells 50 microgram fusidic acid per ml were combined with 100 microgram polyene antibiotic per ml. Bleomycin (10 microgram/ml), which alone did not affect cellular DNA synthesis, inhibited DNA synthesis of V79 cells by more than 90% of the control activity when combined with only 1 microgram pentamycin per ml, whereas a similar extent of inhibition in AMBR cells was observed by combination with more than 5 microgram pentamycin per ml.

Amphotericin B↗

PubMed1997

Diversity of lipid-based polyene formulations and their behavior in biological systems.

Patients with cancer and infectious disease often display dyslipidemias that result in changes in their plasma lipoprotein-lipid composition. It is likely that the interactions of liposomal polyenes with plasma lipoproteins may be responsible for the far different pharmacokinetics and pharmacodynamics of these compounds when they are administered to infected patients rather than to animals or healthy volunteers. Amphotericin B (AmpB) and nystatin are examples of such polyenes. Amphotericin B initially distributes with the high-density lipoprotein (HDL) fraction upon incubation in plasma. Over time, AmpB redistributes from HDLs to low-density lipoproteins (LDLs). This redistribution appears to be regulated by lipid transfer protein. However, when AmpB is incorporated into liposomes composed of negatively or positively charged phospholipids, not only is the capability of LTP to transfer AmpB from HDL to LDL diminished, but AmpB remains retained with only the HDL fraction. However, when liposomal nystatin is incubated in plasma, over 50% of nystatin distributes with HDLs. Over time, nystatin redistributes from HDL to the lipoprotein-deficient plasma fraction, which is composed of mainly aqueous plasma proteins. The lipid composition selected for the drug appears to be a vital constituent in regulating the drug's interaction with biological fluids. Furthermore, liposome (or liposomal particle) size, fluidity, and other physiochemical characteristics also play a role in altering the pharmacokinetics and pharmacological effects of lipid-based drug formulations. Armed with this understanding, a rational approach to clinical development of these formulations could be facilitated.

Amphotericin B↗

PubMed1976

The effect of fetal bovine serum on polyene macrolide antibiotic cytotoxicity and antifungal activity.

The relationships between fetal bovine serum (FBS) concentration and polyene macrolide antibiotic cytotoxicity to animal cells and to fungi were evaluated. The toxicity of amphotericin B (AB) and its derivative, amphotericin B methyl ester (AME), toward KB cells was found to be directly related to fetal bovine serum concentration. At higher FBS levels, increased concentrations of AB and AME were required to reduce 72-hr KB viable cell numbers of 50% of control values. Similarly, polyene macrolide antibiotic levels required to inhibit the growth of Saccharomyces cerevisiae to 50% of controls, and for obtaining minimum fungicidal concentrations (MFC), were greater when higher levels of FBS were used. In addition, AME was less toxic than AB toward KB cells grown in media containing 2, 5, 10, 15 or 20% FBS, whereas the antifungal activities of AB and AME were similar. AME was also capable of eliminating Candida albicans, Saccharomyces cerevisiae, Aspergillus niger or Fusarium moniliforme from KB cultures at antibiotic levels which exhibited less cell toxicity than did the concentrations of AB required for a similar response. These findings indicate that AME may be a potentially useful antifungal antibiotic for tissue culture systems.

Amphotericin B↗

PubMed2005

Biosynthesis of the polyene macrolide antibiotic nystatin in Streptomyces noursei.

The polyene macrolide antibiotic nystatin, produced commercially by the bacterium Streptomyces noursei, is an important antifungal agent used in human therapy for treatment of certain types of mycoses. Early studies on nystatin biosynthesis in S. noursei provided important information regarding the precursors utilised in nystatin biosynthesis and factors affecting antibiotic yield. New insights into the enzymology of nystatin synthesis became available after the gene cluster governing nystatin biosynthesis in S. noursei was cloned and analysed. Six large polyketide synthase proteins were implicated in the formation of the nystatin macrolactone ring, while other enzymes, such as P450 monooxygenases and glycosyltransferase, were assumed responsible for ring "decoration". The latter data, supported by analysis of the polyene mixture synthesised by the nystatin producer, helped elucidate the complete nystatin biosynthetic pathway. This information has proved useful for engineered biosynthesis of novel nystatin analogues, suggesting a plausible route for the generation of potentially safer and more efficient antifungal drugs.

Antifungal Agents↗

PubMed1976

Stoichiometry of hemolysis by the polyene antibiotic lucensomycin.

The stoichiometry of hemolysis by the polyene antibiotic lucensomycin was investigated. It appears that hemolysis occurs only when a relatively high fraction (probably between 15 and 40%) of the cholesterol sites in the erythrocyte membrane have combined with the polyene. Also in phospholipid-cholesterol vesicles the increase of permeability requires occupancy of 40-50% of the existing cholesterol sites. As for the possible cooperative effect in the hemolytic process, it is probable that several (at least 9-10) lucensomycin-cholesterol adducts must interact on each side of the membrane to form an aqueous channel; the distribution of these adducts in the erythrocyte membrane occurs, however, apparently at random.

Animals↗

PubMed1981

Potential-dependent formation of single conducting ion channels in lipid bilayers induced by the polyene antibiotic levorin A.

The aromatic polyene antibiotic levorin A2 forms ion channels permeable to monovalent cations, in lipid membranes containing cholesterol or ergosterol. Channel conductivity is in the range 0.3-0.5 pS. The channel has two main states: conducting (open) and nonconducting (closed). The potential-dependent formation of levorin A2 channels is observed in lipid membranes. The system responsible for the ion-channel selectively is localized on the hydrophilic side of the lactone ring of the polyene molecule.

Antifungal Agents↗

PubMed1985

Interaction of the polyene antibiotic etruscomycin with large unilamellar lipid vesicles: binding and proton permeability inducement.

The effect of the polyene antibiotic etruscomycin on the permeability of large unilamellar lipid vesicles was investigated. Proton leakage was induced in egg-yolk phosphatidylcholine (EPC) vesicles only when sterol was present in the membrane; the extent of leakage was limited. High etruscomycin/lipid ratios (R) were necessary (R greater than 0.1). Higher percentages of sterol increased the permeability, slightly more strongly for ergosterol than for cholesterol. Dipalmitoylphosphatidylcholine (DPPC) vesicles were more sensitive to permeability inducement, even in the absence of sterol in the bilayer (inducement for R greater than 0.06). The interactions of etruscomycin with the vesicles were examined by circular dichroism, fluorescence and 31P-NMR. In the range of antibiotic concentration where permeability was induced, R greater than 0.1 for EPC vesicles, R greater than 0.06 for DPPC vesicles, etruscomycin exhibited characteristic circular dichroism spectra independent of the presence of sterol. Under the same conditions, 31P-NMR and fluorescence studies indicated a destruction or a fusion of the vesicle bilayer. At lower etruscomycin concentrations (R less than 0.03), the etruscomycin circular dichroism spectra were different, indicating that the interaction with membranes containing ergosterol differed from that with membranes containing cholesterol. From correlating the increase in fluorescence intensity with this interaction, as well as from exchange experiments, it was inferred that etruscomycin at a low antibiotic/lipid ratio is more strongly bound to ergosterol-containing vesicles than to cholesterol-containing vesicles. These results and their comparison with the results obtained with other polyene antibiotics indicate that at low R etruscomycin resembles amphotericin rather than filipin in its preferential binding to ergosterol-containing vesicles. At higher R, that is in conditions where permeability is induced, the selectivity is different. The corresponding mechanism seems not to involve the formation of an etruscomycin-sterol channel, since the hydrophobic chain of the complex would be too short to form a channel.

Antifungal Agents↗

PubMed1986

Synergistic incorporation of daunorubicin in erythrocytes in the presence of polyene antibiotics. Role of the membrane potential.

The synergistic incorporation into red blood cells of the antitumor compound daunorubicin, in the presence of the polyene antibiotics amphotericin B and vacidin A, depended on the composition of the external medium. Synergism was observed only for concentrations of polyene antibiotics that induce cation permeability. The same synergistic effect was observed with the K+ selective carrier, valinomycin, but this had a different dependence on the external medium composition. By using the membrane probe 3,3'-dipropylthiadicarbocyanine (diS-C3-(5], the synergistic effect was shown to occur under conditions where addition of the ionophores leads to hyperpolarization of the membrane.

Amphotericin B↗

PubMed2006

Selective lysis of erythrocytes infected with the trophozoite stage of Plasmodium falciparum by polyene macrolide antibiotics.

The continuous increase in strains of the human malaria parasite Plasmodium falciparum resistant to most front-line antimalarial compounds is reason for grave clinical concern. The search for new drugs led us to investigate a number of membrane active polyene macrolide antibiotics, such as amphotericin B, nystatin, filipin and natamycin. The interaction of these compounds with sterols in bilayer cell membranes can lead to cell damage and ultimately cell lysis. The malaria parasite modifies the host erythrocyte membrane by changing the protein and lipid composition and thus the infected cell could be a selective target for membrane active compounds. We found that erythrocytes infected with the trophozoite stage of P. falciparum were particularly susceptible to lysis by amphotericin B (Fungizone) and, to a lesser extent, nystatin, as determined by ELISA and various microscopy assays. Liposomal amphotericin B (AmBisome) displayed a similar specificity for parasitised erythrocytes, but complete lysis required a longer incubation period. In contrast, filipin and natamycin did not distinguish between normal and parasite-infected erythrocytes, but lysed both at similar concentrations. In addition, when added to ring-stage cultures, the amphotericin B preparations and nystatin produced a marked disruption in parasite morphology in less than 2 h without an accompanying permeabilisation of the infected host cell, suggesting a second plasmodicidal mode of action. The results imply that selected polyene macrolide antibiotics or their derivatives could find application in the treatment of severe malaria caused by of P. falciparum.

Amphotericin B↗

PubMed1993

Inactivation by ionizing radiation of ion channels formed by polyene antibiotics amphotericin B and nystatin in lipid membranes: an inverse dose-rate behavior.

The phenomena reported are part of a study about the effects of ionizing radiation on membrane transport. We found that the conductance of lipid membranes in the presence of the polyene-antibiotics nystatin or amphotericin B is reduced to virtually zero following irradiation. Ion channels formed by these substances seem to represent extremely sensitive structures being inactivated by radiation doses in the range of a few Centigray (1 cGy = 1 rad) at sufficiently small dose rates. Inactivation shows a so-called inverse dose-rate behavior, i.e., at constant radiation dose the effect increases with decreasing dose rate. Similar to radiation-induced lipid peroxidation the phenomenon may be understood on the basis of a radical chain mechanism initiated by free radicals of water radiolysis. The process--via peroxidation of the polyene part of the molecules--is suggested to modify the hydrophobic exterior and to destabilize the barrel-like structure of the ion channels.

Amphotericin B↗

PubMed2000

Electronic structure and nonlinear optical properties of model push-pull polyenes with modified indanone groups: a theoretical investigation

Several model polyenes with modified indanone groups were studied by means of density functional theory (DFT) B3LYP/6-31G*, ab initio HF/3-21G* and semiempirical AM1 methods. We investigated the effect of several substituents upon the relationship between the structure, spatial distribution of the highest occupied and the lowest unoccupied pi-MOs, a concept of the global softness and the global hardness as well as both linear and nonlinear polarizabilities for the set of pi-electron chromophores represented by the short-chain model polyene (butadiene) carrying out p-methoxyphenyl group on the one end and several modified indanone groups on the opposite end of the molecule. As probing endocyclic groups used to modify the structure of indanone the following substituents: > CH2; > C=O; > SO2, > C=CH(NO2) and > C=C(CN)2 were selected. The cubic relationship between the polarizability and the global softness was found. The highest polarizabilities (alpha, beta, gamma) are predicted for the derivatives with > C=C(CN)2 group. It was found that the value of beta depends mainly on the difference between dipole moments in the excited and ground states of the molecules. In the case of > SO2 group the results of AMI calculations significantly deviate from relationships found for other derivatives. Experimental IR and Raman spectra of newly synthesized indandione derivative of cinnamaldehyde were compared with computed ones.

Journal Article↗

PubMed2003

Polyene and cytokine treatment of experimental aspergillosis.

The aim of the present study was to assess the efficacy of amphotericin B (AMB), AMB-intralipid admixture (AMB-IL) or nystatin-IL formulation (Ny-IL) in combination with granulocyte colony stimulating factor (G-CSF) in treatment of experimental murine aspergillosis. ICR mice were immunosuppressed by cyclophosphamide and 3 days later inoculated intravenously (i.v.) with Aspergillus fumigatus. Treatment was initiated 2 h later and administered for 5 consecutive days (polyenes, i.v.; G-CSF, intraperitoneally). Combination therapy, particularly G-CSF with AMB or AMB-IL, significantly increased the survival rate (up to 87.3%) and prolonged the mean survival time (MST) (up to 28.8 days) in comparison to untreated controls (0% survival, MST 6.7 days) and to treatment with polyenes alone (up to 51.5% survival, MST 18.4 days). These data indicate that combination therapy could be beneficial for management of disseminated aspergillosis in humans.

Amphotericin B↗

PubMed2003

Direct synthesis of soluble, end-functionalized polyenes and polyacetylene block copolymers.

The ring-opening metathesis polymerization (ROMP) of 1,3,5,7-cyclooctatetraene (COT) in the presence of a chain transfer agent (CTA) with a highly active ruthenium olefin metathesis catalyst resulted in the formation of soluble polyenes. Small molecule CTAs containing an internal olefin and a variety of functional groups resulted in soluble telechelic polyenes with up to 20 double bonds. Use of polymeric CTAs with an olefin terminus resulted in polyacetylene block copolymers. These materials were subjected to a variety of solution and solid phase characterization techniques including (1)H NMR, UV/vis, and FT-IR spectroscopies, as well as MALDI-TOF MS and AFM.

Journal Article↗