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PubMed2002

Multiple relaxation pathways in push-pull polyenes.

Subpicosecond absorption and gain spectroscopy are used to investigate the excited-state behavior of push-pull polyenes made of a diethylthiobarbituric acid electron-acceptor group and a dibutylaniline electron-donor group linked by a pi-conjugated chain. Four polyenes of increasing length, ranging from n = 2 to 5 double bonds, are compared. The relaxation path and relaxation kinetics are studied in dioxane and in cyclohexane, a polar and a nonpolar solvent, respectively. In dioxane, the results provide evidence for the formation of an emissive transient state on an ultrashort time scale (2-3 ps) attributed to a charge transfer (CT) state. The regular shift of the gain peak of this transient state with increase in the chain length (ca. 100 nm per added double bond) indicates that its structure is similar to that of a cyanine, i.e. with a fully conjugated polyenic chain. Its lifetime ranges from a few tens to a few hundreds of picoseconds depending on the chain length. When the number of double bonds increases from n = 2 to 3, the lifetime increases, then decreases continuously for longer chains. In cyclohexane, where the transient CT state is not formed, the decay of the initial excited state follows the same trend when the chain length increases but the lifetimes are shorter than that of the CT state in dioxane. In both solvents, the characterization of long-lived photoproducts by synchronizing two low repetition-rate subpicosecond laser systems demonstrates a change in the relaxation route as the chain length increases. Isomerization occurs for n = 2, whereas intersystem crossing to the triplet state occurs for n = 4. The change in the relaxation channel is observed for n = 3 in both solvents with however a solvent-dependent behavior. In dioxane, relaxation to the triplet state is already observed for n = 3, while an intermediate regime with a relaxation directly to the ground state is observed in cyclohexane. The photophysics of the studied push-pull polyenes is tentatively compared to that of polymethine cyanines and substituted carotenoids.

Journal Article↗

PubMed2004

On the ordering of the first two excited electronic states in all-trans linear polyenes.

Reported experimental evidence of the relative position of the first two excited electronic states in linear polyenes was carefully examined and compared with that derived from time dependent density functional theory (TDDFT) theoretical calculations performed at the B3LYP level on optimized geometries. The energy values for the first two triplet states 3Bu and 3Ag, obtained from TDDFT calculations, were found to be highly strongly correlated with the experimental values. Also, the theoretical calculations for the electronic transition 1 1Ag --> 1 1Bu were also extremely well correlated with their experimental counterparts; even more important, the three reported experimental data for 1 1Ag --> 2 1Ag transitions in these systems conformed to the correlation for the TDDFT 1 1Ag --> 1 1Bu transition. The first excited electronic state in the linear polyenes studied (from ethene to the compound consisting of 40 ethene units, P40) was found to be 1Bu. The energy gap between the excited states 2 1Ag and 1 1Bu decreased with increasing length of the polyene chain, but not to the extent required to cause inversion, at least up to P40. In the all-trans linear polyenes studied, the widely analyzed energy gap from the ground electronic state to the first excited singlet state for infinitely long chains may be meaningless as, even in P40, it is uncertain whether the ground electronic state continues to be a singlet.

Journal Article↗

PubMed1978

Synergism of polyene antibiotics with 5-fluorocytosine.

The synergism of 5-FC with 4 polyene antibiotics, amphotericin B (amph. B), candicidin, trichomycin and nystatin were investigated in 3 in vitro models measuring the fungistatic and fungicidal activity as well as the development of resistant mutants. In these 3 models candicidin and trichomycin exerted a higher synergistic effect than amph. B or nystatin. In vivo (systemic treatment of septicemic candidiasis of the mouse) the combination of 5-FC with amph. B was, however, the most effective. Only with this combination a complete cure (culturally negative) was observed. For topical treatment of Candida vaginitis in rats, the combination of 5-FC with candicidin proved the most active. As far as the biochemical basis of synergism is concerned in Candida albicans in the presence of polyene antibiotics, the incorporation of fluorinated pyrimidines was increased and the reduction of uptake of histidine by 5-FC alone, significantly enhanced. These effects could not be observed in Cryptococcus neoformans. The release of amino acids, phosphate and potassium caused by polyenes was significantly more pronounced in cells pretreated with 5-FC. Thus, the interaction between 5-FC and the polyenes may, in fact be, mutual.

Amino Acids↗

PubMed1976

Determination of mycelial steroids with the aid of polyene antibiotics. II. Quantitative determination of the mycelial steroids of Mucor hiemalis.

UV absorption spectrum of polyene antibiotics was dramatically altered in the presence of steroids. The introduction of a steroid to an aqueous solution of polyene antibiotics resulted in a change in the ratio of absorbance of peak 3 (with shorter wavelength) to peak 1 (with longer wavelength), E3/E1. Interactions between 28 steroids and 4 polyene antibiotics were studied and the results revealed that the structures of steroids essential for the optimal interaction with polyene antibiotics were C-17 side chain, substitution C-3 hydroxyl group, intact steroid nucleus and aromatic A-ring. The ratio of E3/E1 was used for the determination of steroids in mycelium of Mucor hiemalis and the result was in good agreement with that obtained from gas chromatograph. The (-) strain had a greater change in the ratio of absorbance, E3/E1, than that of the (+) strain. The ratio of absorbance, E3/E1, decreased in the following order: the (-) strain, the (-) strain with the addition of the filtrate of (+) strains, the mated strains, the (+) with the addition of the filtrate of (-) strain and the (+) strain.

Amphotericin B↗

PubMed1991

Polyene antibiotics in the membrane environment.

The cytotoxic activity of the polyene antibiotics mainly depends on the appearance of the drug species which arises from drug-sterol complexation. The unsaturation and intact macrolide ring of the polyenes are the requirements for the biological activity. All the polyene antibiotics can form the complex with the sterol having 3 beta-OH group, and planar ring and a hydrophobic side chain. Aromatic polyene antibiotics with positively charged head group have been considered as most potential antifungal agents.

Amphotericin B↗

PubMed1975

[Effect of polyene macrolide antibiotics on normal and cell wall deficient Escherichia coli W1655F+ cells].

The polyene macrolide antibiotics are active against yeast, fungi, and other eukaryotic cells, but are with a few exceptions inactive against bacteria. The resistance of bacteria against these compounds is usually explained by the absence of sterols in their cells, the target sites of polyene antibiotics. However, in our experiments with mycotrienin, nystatin, tetramycin, lucenosmycin, rimocidin, filipin, lagosin, flavofungin, flavomycoin, antibiotic 2814P, antibiotic 5001P, and candicidin it was demonstrated that bacteria may be susceptible to polyene antibiotics, too, if the wall-less stable protoplast type L-form of E. coli W1655F+ is used. The measured growth inhibition concentrations were comparable with those of typical antibacterial antibiotics. Our experiments have shown that the normal rod form and the wall-less L-form of E. coli W1655F+ contain traces of sterols in nearly the same concentration range. This means that the selective sensitivity of the L-form cannot be explained by higher sterol content of these cells in comparison to the resistant normal rod form cells. We assume that the bacterial cell wall is responsible for the resistance of the normal rod form by masking internal target sites.

Anti-Bacterial Agents↗

PubMedDate not supplied

In vivo and in vitro antifungal activity of the polyene derivative SPA-S-753 against encapsulated form of Cryptococcus neoformans.

The in vitro and in vivo activity of SPA-S-753 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diaspartate), a new water soluble polyene, was compared with amphotericin B against Cryptococcus neoformans in encapsulated (K) and nonencapsulated (N) morphological forms. In vitro tests against 17 isolates of C. neoformans (in K or N form) showed that SPA-S-753 activity is about ten times higher than that of amphotericin B. In direct contact tests the SPA-S-753 cytocidal action was significantly higher than that of amphotericin B; the K cells are, however, less sensitive to the cytocidal action exerted by the two polyenes even when using concentrations 4-fold higher than those used against the N cells and they present a smaller potassium ion release. The cytocidal activity of the two polyenes is favoured by a low electrolyte concentration and an acid pH. SPA-S-753 microbicidal activity by contact in vivo, in mice infected with C. neoformans N cells by i.p. route, is more powerful than that of amphotericin B. In protection tests in mice infected with 10 LD50 of C. neoformans K cells, SPA-S-753 action is again more powerful, but not to a significant degree, than that of amphotericin B. In conclusion, both substances showed a reduced in vitro and in vivo activity against C. neoformans in the K morphological form. Nevertheless our results demonstrate that SPA-S-753 exerts an antifungal overall activity that is more effective than that of amphotericin B under similar experimental conditions.

Amphotericin B↗

PubMed2002

Polyene antibiotic biosynthesis gene clusters.

Over the past 15 years the biosynthetic gene clusters for numerous bioactive polyketides have been intensively studied and recently this work has been extended to the antifungal polyene macrolides. These compounds consist of large macrolactone rings that have a characteristic series of conjugated double bonds, as well as an exocyclic carboxyl group and an unusual mycosamine sugar. The biosynthetic gene clusters for nystatin, pimaricin, amphotericin and candicidin have been investigated in detail. These clusters contain the largest modular polyketide synthase genes reported to date. This body of work also provides insights into the enzymes catalysing the unusual post-polyketide modifications, and the genes regulating antibiotic biosynthesis. The sequences also provide clues about the evolutionary origins of polyene biosynthetic genes. Successful genetic manipulation of the producing organisms leading to production of polyene analogues indicates good prospects for generating improved antifungal compounds via genetic engineering.

Anti-Bacterial Agents↗

PubMed1990

Early membrane potential and cytoplasmic calcium changes during mitogenic stimulation of WEHI 231 cell line by polyene antibiotics, lipopolysaccharide and anti-immunoglobulin.

Changes in free cytosolic calcium concentration and in membrane voltage are thought to be important initiating events in lymphocyte activation. The antifungal agent amphotericin B (AmB) holds interesting immunomodulating properties and its N-thiopropionyl derivative (AmBSH) is a potent polyclonal B-cell activator. These molecules may then exert their stimulating activity through the production of early ionic signals similar to those delivered by the classical activators lipopolysaccharide (LPS) and anti-immunoglobulin (anti-Ig). We addressed this question in a B-cell line (WEHI 231) which has previously been shown to exhibit characteristic response to LPS and anti-Ig. AmBSH protected these cells against anti-Ig-induced cell growth inhibition, providing a LPS-like response. In contrast, the parental compound AmB did not. The two polyene antibiotics did not modify the resting Ca2+i level of the cells, neither did LPS, whereas anti-Ig induced a rapid increase in the cytosolic calcium concentration. On the other hand, polyene antibiotics and LPS promoted membrane depolarization, whereas membrane voltage remained unchanged after anti-Ig treatment. Polyene antibiotics-induced depolarization originated from the increase of membrane permeability to Na+ ions and occurred independently of Ca2+i changes. The relationship between membrane potential and Ca2+i changes in lymphocyte activation are discussed on the basis of these results. Our conclusion was that constitutive Ca2+(-)dependent K+ channels are absent in the WEHI 231 cell line.

Amphotericin B↗

PubMed2006

Interaction between nystatin and natural membrane lipids in Langmuir monolayers--the role of a phospholipid in the mechanism of polyenes mode of action.

Nystatin (NYS), a polyene antifungal antibiotic, has been investigated in Langmuir monolayers alone and in mixtures with mammalian and fungi membrane sterols (cholesterol and ergosterol, respectively) as well as with a model phospholipid (DPPC). The interactions between film molecules have been examined both in a qualitative and quantitative way with the excess area per molecule (AExc), excess free energy of mixing (DeltaGExc) and the interaction parameter (alpha). The obtained results have been compared with those previously reported for another polyene antimycotic: amphotericin B (AmB) mixed with lipids. Higher affinity of NYS has been observed for ergosterol vs. cholesterol, however, the strongest attractions were found for its mixtures with DPPC. The obtained results have been verified with biological studies reported previously for both antibiotics (NYS and AmB). A thorough analysis of the Langmuir experiment results performed for both polyenes enabled us to conclude that the presence of DPPC can be considered as a key factor affecting their antifungal activity as well as their toxicity towards host cells.

Amphotericin B↗

PubMed2005

A tailoring activity is responsible for generating polyene amide derivatives in Streptomyces diastaticus var. 108.

We recently characterized rimocidin B (3b) and CE-108B (4b) as two polyene amides with improved pharmacological properties, produced by genetically modified Streptomyces diastaticus var. 108. In this work, genetic and biochemical analysis of the producer strain show that the two amides are derived from the parental polyenes rimocidin (3a) and CE-108 (4a) by a post-PKS modification of the free side chain carboxylic acid. This modification is mediated by an amidotransferase activity operating after the biosynthesis of rimocidin (3a) and CE-108 (4a) are completed. Two polyenes, intermediates of the biosynthetic pathway of rimocidin (3a) and CE-108 (4a), were also isolated and shown to have some improved pharmacological properties compared with the final products.

Amides↗

PubMed1994

Cation conductance and efflux induced by polyene antibiotics in the membrane of skeletal muscle fiber.

Cation conductance and efflux induced by polyene antibiotics amphotericin B (AMB), amphotericin B methyl ester (AME), nystatin, mycoheptin, and levorin on frog isolated skeletal muscle fibers and whole sartorius muscles were investigated. Conductance was measured under current-clamp conditions using a double sucrose-gap technique. Cation efflux was studied using flame emission photometry. Some new data were obtained concerning the effects of levorin and mycoheptin on biological membranes. The power dependence of polyene-induced cation transport on antibiotic concentration in muscle membrane was lower than that in bilayers. The decline in the equilibrium conductance caused by polyene removal (except for levorin) was very fast. There was reverse temperature dependence of AMB- and nystatin-induced conductances. Both induced conductance and efflux values demonstrated a correlation with the order of antifungal activities: levorin > AMB, mycoheptin > AME > nystatin, except for AME, which was more potent on yeastlike cells. These effects were interpreted in terms of possible differences in the kinetics of channel formation in biological and model membranes and in light of the role of nonconducting antibiotic forms in biological membranes.

Amphotericin B↗

PubMed2003

Efficient biomimetic catalytic epoxidation of polyene polymers by manganese porphyrins.

Two polyene polymers, cis-polybutadiene and cis-polyisoprene, were transformed into polyepoxides under mild conditions. The epoxidation of these two polyene polymers is stereospecific, giving cis-epoxides as products. All factors controlling the reaction rate, such as the nature of the catalyst, the oxygen donor and the presence of bases as axial ligands, were studied. The optimum results were obtained when iodosylbenzene was used as the oxygen donor, Mn(TpFPP)Cl as the catalyst and imidazole as the axial ligand. Under these optimum conditions the turnover number was found to be 71. These results render this system promising for the epoxidation of polyene polymers in a more general way.

Catalysis↗

PubMed2004

Novel polyene carboxylic acids from Streptomyces.

Reinvestigation of the production of the unusual polyene carboxylic acid serpentene (1a) from Streptomycessp. Tü 3851 revealed the presence of additional polyene carboxylic acids. The methyl esters of the new all-trans serpentene (2) and four new dicarboxylic acids (3-6) were isolated after methylation of the isolated polyene fraction. The dicarboxylic acids might result from omega- and beta-oxidation of the parent compounds 1 and 2.

Carboxylic Acids↗

PubMed2003

Photochemical reactivity of polyenes: from dienes to rhodopsin, from microseconds to femtoseconds.

In reviewing the photochemistry of polyenes (from dienes and trienes to the visual retinyl chromophore), we categorize condensed-phase photochemical reactivity of molecules into two groups: those from thermally equilibrated excited species and those from unequilibrated excited species. Classical theories on radiationless transitions are useful for rationalizing the reactivity of molecules belonging to the first set only. The second group includes many of the exciting ultrafast photochemical reactions reported recently for polyenes (including dienes and trienes), in some cases with rates faster than vibrational relaxation. Much of the excited singlet-state reactions of polyenes, including the Hula-twist mechanism of photoisomerization, have been integrated with concepts introduced in other ultrafast spectroscopic/photochemical studies. Taking into consideration the special environment of the retinyl chromophore in rhodopsin, we propose a new mechanism for the phototrigger that accounts for its unusually fast rate of isomerization.

Free Radicals↗

PubMed2004

A unified approach to polyene macrolides: synthesis of candidin and nystatin polyols.

Polyene macrolide antibiotics are naturally occurring antifungal agents. Members of this class include amphotericin B, which has been used widely to treat systemic fungal infections. A general synthetic strategy has been devised to prepare polyol chains associated with the polyene macrolides. Cyanohydrin acetonide alkylations were used to assemble the carbon skeleton, and a simple modification of the strategy allowed an advanced intermediate to be converted to either the candidin polyol or the nystatin polyol. The candidin polyol was further elaborated to a protected candidin aglycone. This strategy will be applicable to other members of the polyene macrolide natural products.

Antifungal Agents↗

PubMed1987

The effects of azole and polyene antifungals on the plasma membrane enzymes of Candida albicans.

The two clinically important classes of antimycotic drugs, the polyenes and azoles, act on the plasma membrane of the cell. The primary modes of action are believed to be through interaction with sterols (polyenes) and alteration in sterol composition of the membrane (azoles). In this report we show that, at growth inhibitory concentrations, the polyenes (nystatin and amphotericin) and azoles (miconazole and ketoconazole) also inhibit plasma membrane enzymes. There was extensive (greater than 75%) inhibition of the Candida albicans plasma membrane enzymes ATPase, glucan synthase, adenyl cyclase and 5'-nucleotidase, when assayed in situ. The antifungals papulacandin and echinocandin, which inhibit glucan synthesis, also inhibited plasma membrane enzymes in situ; glucan synthase (greater than 90%), 5'-nucleotidase (greater than 80%) and ATPase (70-80%). Purified plasma membrane was prepared from yeast cells of C. albicans by two different techniques: concanavalin A stabilization and coating of spheroplasts with silica microbeads. In the purified plasma membrane vesicles prepared from concanavalin A the adenyl cyclase and phosphodiesterase were extensively (greater than 90%) inhibited by the three different classes of antifungal drugs; variable inhibition was observed with ATPase (70-100%). The 3',5'-cyclic phosphodiesterase of the plasma membrane purified by the microbeads method was almost completely inhibited by all of the antifungals tested and there was partial inhibition of ATPase (20-85%) and adenyl cyclase (30-90%).

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Methods for the recovery and purification of polyene antifungals.

Despite the development of newer antifungal drugs, the polyene antifungals continue to be the most potent broad-spectrum fungicides available for clinical use. The incidence and severity of fungal infections are on the rise, underscoring the need for new and more effective antifungal drugs. Thus, the search for new polyene antifungals is ongoing. The limited solubility, polymorphic character, and inherent chemical instability of these compounds make their economical recovery and purification from mass culture challenging problems in biotechnology. This article provides a comprehensive review of the methods that have been developed for the recovery and purification of amphotericin B and nystatin, the two most important polyenes currently in clinical use.

Amphotericin B↗