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PubMedDate not supplied

[Composition and certain properties of Candida albicans cells with a low level of resistance to polyene antibiotics].

The lipid and protein composition of Candida albicans, strain R3, with a low resistance to polyene antibiotics does not differ much from that of the parent, susceptible culture. Nevertheless, the rate of potassium release from the cells and the incorporation rate of 14C-amino acids in the cells of C. albicans, strain R3, under the action of amphotericin B are lower as compared to the susceptible culture; therefore, the resistance of C. albicans, strain R3, must be due to a decrease in the degress of its disordered selective permeability. Sterols isolated from the cells in both strains were found to be capable of binding to polyenes at a high rate in solution. However, sterols from the strain R3 with a low resistance to polyenes, when incorporated into a synthetic lipid membrane, increase its permeability slower than sterols from the susceptible strain, which suggests that sterols from the low-resistant strain R3 are possibility involved in the phenotypic manifestation of resistance.

Amphotericin B↗
PubMedDate not supplied

Free radical damage to polyene antifungal antibiotics: changes in biological activity and thiobarbituric acid reactivity.

Polyene antifungal antibiotics contain thiobarbituric acid-reactive substances suggestive of the presence of peroxidic compounds. These peroxides appear to play no part in the drug's antifungal activities. The polyenes were relatively stable to further oxidation in air, but lost biological activity and native ultraviolet absorption upon irradiation with ultraviolet light or incubation with iron salts. No evidence was found for the participation of hydroxyl radicals in the observed damage to the polyene molecules. However, organic oxygen radicals were implicated and protection against ferrous salt dependent damage could be afforded by the addition of the antioxidant propylgallate.

Air↗
PubMedDate not supplied

[Long-term effect of polyenic-fatty-acids-enriched diet on the relations of fatty acids and glycerophospholipids in 50- to 60-year-old HLP patients].

Seventy-seven patients (twenty-nine males and forty-eight females aged fifty to sixty) with primary HLP type IIa, IIb, IV were treated for eight months with polyenic fatty acids enriched metabolic basis diet. Gas chromatographic analyses of the fatty acid pattern of glycerophospholipids were carried out in 4-monthly intervals. It was found an increase of polyenic fatty acids and a decrease of saturated and monoenic fatty acids in all three types of HLP. Polyenic fatty acids enriched metabolic basis diet influences favourable atherogenic fatty acids constellations of the glycerophospholipids.

Age Factors↗
PubMed1981

[Increase in the specific activity of killed influenza vaccines by using polyene antibiotics].

It was shown experimentally that polyenic antibiotics, i. e. amphotericin B and sodium levorin markedly increased the specific immunogenic properties and interferonogenic activity of inactivated influenza virus vaccine prepared with various methods from highly reproductive recombinants. The rate of pneumonia and death from influenza among the vaccinated mice treated with inactivated influenza virus vaccine and one of the polyenic antibiotics was lower than that among the animals treated with the vaccine alone (P less than 0.05). Correlation between the increase in the immunological response, the decrease in the virus reproduction rate in the lungs and addition of the antibiotics into the vaccine was also observed. It is recommended that inactivated influenza virus vaccine be used in conjunction with polyenic antibiotics.

Amphotericin B↗
PubMed2026

Oxidative stress induces E. coli aryl polyene expression, sensitizing the bacterial stress response and modulating the redox environment of innate immune cells.

UNLABELLED: Aryl polyenes (APEs) are specialized polyunsaturated outer membrane lipids that protect their producers from oxidative stress and contribute to biofilm formation. APEs are produced by an abundant biosynthetic gene cluster (BGC) family conserved across Gram-negative bacterial clades. The APE biosynthesis pathway involves 11 different enzymes and culminates in the attachment of APEs to an anchor molecule in the Gram-negative outer membrane. Unlike most other small molecule BGCs, the APE BGC does not contain a dedicated regulatory gene that controls the production of its metabolically costly compounds. Building from our prior observations of APEs' role in acute oxidative stress protection, we use a uropathogenic Escherichia coli (UPEC) strain to show that APE expression conveys a potential competitive advantage characterized by increased early-stage growth, sensitization of the bacterial oxidative stress response, and dampening of the redox stress of innate immune cells after in vitro infection. Our data indicate that APEs could act as a UPEC fitness factor, and in future work, we aim to study their contribution to overall bacterial pathogenicity and survival, as well as how APEs could facilitate the transition from an oxygen-poor environment, such as the gut, to the oxygen-rich environment of the urinary tract. IMPORTANCE: Bacterial pathogens use various mechanisms to achieve a competitive advantage under harsh conditions, such as during interactions with their host. We studied the function of aryl polyenes (APEs), specialized polyunsaturated fatty acids in the outer membrane, in the context of a uropathogenic E. coli strain. APE expression is induced by an oxidative environment and contributes to early-stage growth and sensitization of the oxidative stress response. Furthermore, APE-expressing E. coli dampen the intracellular oxidative milieu of target host phagocytes. These findings suggest a role for APEs as a fitness factor and create opportunities to study their in vivo function and explore them as a potential drug target.

Oxidative Stress↗
PubMed1975

Synthesis and biological properties of alkyl esters of polyene antibiotics.

Several new alkyl esters of polyene antibiotics were prepared by an improved general procedure, and their toxicity and microbiological activity were tested. Some of these alkyl esters were more active than the nonesterified polyenes against Candida albicans but were less effective than the known methyl esters. Their toxicity was much less than that of the parent compounds.

Animals↗
PubMed1976

Relationship between acute toxicity in mice and polymorphic forms of polyene antibiotics.

Marked differences in LD50 values were found between various batches of polyene antibiotics (mepartricin and nystatin) after intraperitoneal administration in suspension to mice. Such differences do not seem attributable to the particle size but to different molecular spatial arrangements of the products, which modify their solubility and biological availability. In the samples obtained by chemical treatments of some batches of the polyene substances, it has been possible to change the toxicity drastically and then to bring it back to its original value.

Animals↗
PubMed1978

Sterol-polyene antibiotic complexation: probe of membrane structure.

Polyene antibiotics are useful tools for studying the role of sterols in biological membranes. The interaction of polyene antibiotics with membrane-bound sterols in artificial membrane systems, prokaryotic and eukaryotic cells, and lipid-containing viruses is reviewed. The pentaene macrolide, filipin, is shown to serve as a probe of phosphatidylcholine-sterol interaction and of the localization of cholesterol in the membrane of mycoplasmas.

Amphotericin B↗
PubMed1976

Effect of the lipid composition of Mycoplasma mycoides subspecies capri and phosphatidylcholine vesicles upon the action of polyene antibiotics.

(1) The effects of filipin and amphotericin methyl ester upon the K+ efflux from Mycoplasma mycoides subsp. capri and egg lecithin sonicated vesicles were investigated. Both the nature of the sterol and the composition of the membranes affected the sensitivity to each polyene antibiotic. (2) M. mycoides subsp. capri containing ergosterol was much more sensitive to amphotericin methyl ester than cells containing cholesterol. Cholesterol-containing cells were about twice as sensitive to filipin as the ergosterol-containing cells. These results were confirmed with phosphatidylcholine vesicles. (3) At 2 degrees C the filipin sensitivity of M. mycoides subsp. capri was independent of the membrane cholesterol content and the sensitivity towards amphotericin methyl ester decreased when the membrane cholesterol content was increased, in contrast to the results at 20 degrees C. (4) At 2 degrees C, sterol-free egg lecithin vesicles became very sensitive to both filipin and amphotericin methyl ester and the presence of cholesterol in the vesicles did not increase the sensitivity further. At high concentrations of cholesterol (greater than 30 mol%), the polyene antibiotic sensitivity, particularly towards amphotericin methyl ester, was greatly reduced.

Amphotericin B↗
PubMed1976

Interaction of the polyene antibiotics with lipid bilayer vesicles containing cholesterol.

The interaction of the polyene antibiotics, amphotericin B, nystatin and filipin with cholesterol-containing single bilayer lipid vesicles has been characterized using gel permeation chromatography and proton magnetic resonance. All three antibiotics bind to vesicles at low concentrations without causing a large amount of vesicle destruction. The strength of binding as determined by gel permeation studies is greater for filipin and amphotericin than for nystatin. Nystatin and amphotericin B at these low concentrations induce a rapid loss of internal vesicle contents consistents consistent with pore formation. Filipin induces no leakage beyond that expected from partial vesicle destruction or general detergent action. At antibiotic levels above 1:1 antibiotic: cholesterol ratios the NMR results show all three antibiotics to cause extensive vesicle destruction. The onset of this behavior, which appears to be independent of the total antibiotic concentraion, indicates a well defined antibiotic : cholesterol interaction stoichiometry. Despite the fact that cholesterol is required for antibiotic activity, the NMR spectra prior to vesicle destruction show no changes indicative of an antibiotic-induced reversal of cholesterol restriction of phosphatidylcholine mobility. The contrast with polyene antibiotic behavior in more extended bilayers is discussed.

Amphotericin B↗
PubMed1979

How do ionic channel properties depend on the structure of polyene antibiotic molecules?

A study has been made of the properties of ionic channels formed in phospholipid-cholesterol bilayers by polyene antibiotics of various molecular structures. Properties of channels created by natural antibiotics with different structures of the lactone ring (amphotericin B-nystatin-mycoheptin) as well as by some derivatives of amphotericin B modified with respect to the amino and carboxyl groups are compared. Neutralization of one or both charges of the amphotericin B molecule (both by chemical modification and by pH shift) increases the probability of the channel to be in a nonconducting state. An increase of cholesterol concentration in the membrane produces an opposite effect. It is assumed that the electrostatic interaction of the amino group of an antibiotic molecule with the carboxyl group of an adjacent one stabilized the channel. Conductance and selectivity of an open channel are not influenced by changes in the charged groups. These properties strongly depend on the structure of the polar chain of the lactone ring. For example, the appearance of one more carbonyl group in the mycoheptin molecule results in a sharply decreasing anion permeability of channels. An antibiotic concentration which is necessary to observe single channels depends on the polyene chain structure: this is about 10(-7) M for tetraene nystatin and 2.10(-8) M for heptaene amphotericin B an mycoheptin.

Amphotericin B↗
PubMed1975

Inhibition of cholesterol esterification by polyene antibiotics in blood plasma.

The inhibition of the lecithin-cholesterol acyltransferase reaction in human plasma by the polyene antibiotics, levorine and amphotericin B, has been demonstrated by in vitro experiments. It is suggested that the inhibition of the esterification reaction is the result of interaction between polyenes and non-esterified cholesterol.

Acyltransferases↗
PubMed1991

Polyene antibiotics increase the ionic permeability of synaptosomal plasma membranes.

The effects of antifungal heptaene antibiotics candicidin and amphotericin B were investigated in isolated cerebral cortical nerve terminals (synaptosomes). The synaptosomes were incubated with candicidin or amphotericin B in the presence or absence of external Ca2+. Candicidin (0.4-0.8 I.U./mL) increased intrasynaptosomal free Ca2+ significantly. This increase was not significantly suppressed by 30 microM verapamil or 2 microM nifedipine. In the absence of extrasynaptosomal Ca2+ intrasynaptosomal free Ca2+ was not changed by candicidin. Amphotericin B increased intrasynaptosomal free Ca2+ as well. Candicidin (0.05-0.6 I.U./mL) increased the respiration rate up to 3.5-fold above the basal rate. This response was not affected by the absence of extracellular Ca2+. Ouabain completely blocked the increase of respiration caused by candicidin, whereas tetrodotoxin was ineffective. The plasma membrane depolarized in a dose-dependent manner after candicidin (0.2-0.8 I.U./mL). The mitochondrial membrane potential was little affected and only at the highest concentrations. The results indicate that heptaene polyenes increase synaptosomal ionic permeability, which is reflected in increased Ca2(+)-influx and accelerated respiration. The increment in synaptosomal free calcium takes place probably as a nonspecific leak via typical polyene-cholesterol channels. The respiration is accelerated by increased Na(+)-permeability through the plasma membrane which stimulates the function of Na+, K(+)-ATPase and thus increases the energy demand.

Amphotericin B↗
PubMed1992

Polyene macrolide antibiotics: indirect stimulation of the Na+/H+ exchanger of BALB/c B lymphoid cell line, A20.

The fluorescent pH probe, 2'-7'-bis (carboxyethyl) 5-carboxyfluorescein, was used to follow changes in internal pH (pHi) induced by aromatic polyene antibiotics in the BALB/c lymphoid cell line A20. The antibiotics studied were vacidin, which contains a free carboxylic group in the position C18 of the macrolide ring, and vacidin glycyl methyl ester and perimycin, which are without free carboxylic groups. Although all of them induced transmembrane Na+ and K+ movements, only vacidin had protonophoric activity, as previously demonstrated for red blood cells [Cybulska B et al., Biochem Pharmacol 38: 1755-1762, 1989]. However, with all three antibiotics, pHi changes were observed in A20 cells. It was demonstrated that the transmembrane H+ movements resulted to different degrees, principally in the case of perimycin and vacidin glycyl methyl ester, or partially in the case of vacidin, from the stimulation of the Na+/H+ exchanger by the induced Na+ permeability. The non-aromatic polyene antibiotic amphotericin B had a low ability to increase proton permeability.

Amiloride↗
PubMed1993

Polyene antibiotics inhibit superoxide-producing NADPH oxidase in a polymorphonuclear cell-free system.

We studied the effect of polyene macrolide antibiotics on the NADPH-dependent superoxide production induced by arachidonic acid in a cell-free system consisting of the membrane and cytosolic fractions obtained from bovine polymorphonuclear leukocytes. Preincubation of the membrane fraction with polyenes before addition of the soluble components of the reaction mixture resulted in a dose-dependent inhibition of superoxide production.

Animals↗
PubMed2006

Dynamics of bolaamphiphilic fluorescent polyenes in lipid bilayers from polarization emission spectroscopy.

The rotational motions of the biamphiphilic polyenes (bolapolyenes) dimethyl all-(E)-octacosa-10,12,14,16,18-pentaenedioate (DE28:5) and dimethyl all-(E)-tetratriaconta-13,15,17,19,21-pentaenedioate (DE34:5), with head-to-head distances of 34 and 42A, respectively, have been examined by fluorescence anisotropy methods. The membrane-spanning bolapolyenes, which contain a central emitting pentaene group tethered to two methoxycarbonyl opposite polar heads by symmetric C(8) (DE28:5) and C(11) (DE34:5) polymethylene chains, were dispersed in lipid bilayers of DPPC or DMPC, and the stationary and picosecond-resolved emission was recorded as a function of temperature. In fluid-phase DMPC bilayers, three relaxation times could be determined, assigned to fast (0.2 and 2ns) single-bond isomerization processes localized on the alkyl chains, and to whole-molecule oscillations ( approximately 11ns), respectively. The anisotropy decay parameters were further analyzed in terms of a diffusive model for wobbling in a Gaussian ordering potential, to assess the anchoring effect of the symmetric polar heads. In this way, the average rotational diffusion constant of the bolapolyenes, D( perpendicular), could be estimated as 0.022-0.026rad(2) ns(-1) (DMPC bilayers, 35 degrees Celsius), a value that is only 1/3 of that corresponding to the related pentaene fatty acid spanning a single membrane monolayer. In contrast, the amplitude of the equilibrium orientational distribution (theta(half-cone) approximately 50 degrees ) is very similar for both the transmembrane and the single-headed polyenes. The reorientational oscillations of the central emitting group in the bolapolyenes necessarily would produce large-amplitude (2-5A) and very fast (ns) translational motions of the polar heads.

Lipid Bilayers↗
PubMed2003

Organizational and mutational analysis of a complete FR-008/candicidin gene cluster encoding a structurally related polyene complex.

The complete gene cluster for biosynthesis of a polyene complex, FR-008, spans 137.2 kb of the genome of Streptomyces sp. FR-008 consisting of six genes for a modular PKS and 15 additional genes. The extensive similarity to the partially characterized candicidin gene cluster in Streptomyces griseus IMRU3570, especially for genes involved in mycosamine biosynthesis, prompted us to compare the compounds produced by Streptomyces sp. FR-008 and Streptomyces griseus IMRU3570, and we found that FR-008 and candicidin complex are identical. A model for biosynthesis of a set of four structurally related FR-008/candicidin compounds was proposed. Deletion of the putative regulatory genes abolished antibiotic production, while disruption of putative glycosyltransferase and GDP-ketosugar aminotransferase functionalities led to the productions of a set of nonmycosaminated aglycones and a novel polyene complex with attachment of altered sugar moiety, respectively.

Amino Acid Sequence↗
PubMed2005

Two polyene amides produced by genetically modified Streptomyces diastaticus var. 108.

Streptomyces diastaticus var. 108, a newly isolated strain, was recently characterized as a producer of two polyene macrolide antibiotics (rimocidin and CE-108), and the biosynthetic gene cluster was partially characterized. When the producer strain was genetically modified by transformation with some engineered SCP2*-derived vectors carrying the ermE gene, two previously uncharacterized macrolides were detected in the fermentation broth of the recombinant strain and chemically characterized as the amides of the parental polyene carboxylic acids. The biological activity and some in vitro toxicity assays showed that this chemical modification resulted in pharmaceuticals with improved biological properties compared with the parental products.

Antifungal Agents↗