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PubMed1980

Dissociation between the induction of potassium efflux and cytostatic activity of polyene macrolides in mammalian cells.

The paper contains data on the induction of K+ efflux and viability of baby hamster kidney (BHK-21) cells after their treatment with macrolide antibiotics inducing specific pores in membrane. New water-soluble semisynthetic derivatives of amphotericin B and aureofacin (N-glycosyl and trimethylammonium methyl ester derivatives) as well as the parent compounds were used to compare the concentration of antibiotics inducing permeabilizing and cytostatic effects. We found that a two- to eight-times-higher concentration of polyene antibiotic was required to observe a cytostatic effect than for release of 50% of the cellular potassium (K50 concentration) from BHK-21 cells. These differences were larger for water-soluble derivatives than for the parent compounds. The amount of intracellular potassium in treated cells incubated under optimal growth conditions was higher than in cells which had been further washed with K+-free maintenance medium. The membrane permeability changes induced by low concentrations of specific polyenes were observed to be reversible. BHK-21 cells were able to repair polyene-induced membrane permeability within 3 to 12 h under optimal growth conditions, after cell treatment with K50 concentration of specific macrolide antibiotics. The repair phenomenon is postulated as an explanation for the dissociation observed between permeabilizing and cytostatic effect of specific polyenes in BHK-21 cells.

Amphotericin B↗
PubMed1980

Incidence of polyene-resistant yeasts recovered from clinical specimens.

The development of resistance to amphotericin B and nystatin in yeast isolates was determined. Organisms recovered from patients on the oncology service, undergoing extensive chemotherapy for acute leukemia and bone marrow transplantation, were compared with yeasts recovered from patients on other services in the same hospital over a 7-month period. An agar dilution method was used to assay the susceptibility for each antibiotic; resistance was defined as a minimal inhibitory concentration of greater than or equal to 2 micrograms/ml for amphotericin B and greater than or equal to 16 micrograms/ml for nystatin. None of 625 isolates from 238 patients on non-oncology services demonstrated polyene resistance. Resistance only occurred in a subpopulation of oncology patients, in which 55 isolates (7.4%) from six patients (8.6%) exhibited polyene resistance. Resistance yeasts included Candida albicans (three strains), Candida tropicalis (one strain), and Torulopsis glabrata (two strains). All of the patients from whom resistant yeasts were recovered had experienced extensive chemotherapy with cytotoxic agents, granulocytopenia, and long-term treatment with both antibacterial and polyene antibiotics. Resistance to 2 micrograms of amphotericin B per ml and to 16 micrograms of nystatin per ml was associated with loss or marked depression of ergosterol in the cell membrane as measured by ultraviolet spectra. A significant incidence of polyene resistance in an oncology subpopulation was documented, suggesting a need for susceptibility testing in patients who are at high risk for development of drug-resistant fungal pathogens.

Amphotericin B↗
PubMed1980

Classification of polyene antibiotics according to their synergistic effect in combination with bleomycin A2 or fusidic acid.

Five polyene antibiotics were compared for their effects on colony formation of either Chinese hamster V79 or Saccharomyces cerevisiae cells. A 10 to 40 times higher concentration of amphotericin B (heptaene) or nystatin (degenerated heptaene) was necessary to inhibit colony formation of hamster cells than that needed to inhibit colony formation of yeast cells. In contrast, colony formation of both hamster and yeast cells was inhibited to the same extent by similar concentrations of filipin (pentaene), pentamycin (pentaene), or pimaricin (tetraene). The five polyene antibiotics were also compared for their effects on colony formation of either V79 or S. cerevisiae cells when combined with a nonpolyene antibiotic, fusidic acid or bleomycin A2. Amphotericin B or nystatin could augment the cytocidal effect of fusidic acid but not that of bleomycin A2, whereas pentamycin or pimaricin could augment the cytocidal effect of both fusidic acid and bleomycin A2 against hamster and yeast cells. Filipin was found to enhance the action of fusidic acid and bleomycin upon growth of mammalian cells, whereas the pentaene polyene significantly potentiated the action of fusidic acid, but not that of bleomycin A2, against S. cerevisiae. It was therefore suggested that these polyene antibiotics be classified into two groups: group 1 (pimaricin, pentamycin, and filipin) and group 2 (amphotericin B and nystatin).

Amphotericin B↗
PubMed1961

Alterations in the permeability of Neurospora crassa due to polyene antibiotics.

Kinsky, Stephen C. (Washington University, St. Louis, Mo.). Alterations in the permeability of Neurospora crassa due to polyene antibiotics. J. Bacteriol. 82:889-897. 1961.-Thirty-three antibiotics and synthetic fungicides were examined for their effect on the growth and morphology of Neurospora crassa. Only the polyene antibiotics (nystatin, amphotericin B, and filipin) caused a decrease in the dry weight of mycelial mats, which was accompanied by the appearance of cytoplasmic constituents in the medium. The influence of polyene concentration, incubation time, mycelial age, various metabolic inhibitors, pH, and media composition on this phenomenon are described. The present evidence indicates that the polyenes exert their primarily fungicidal effect by an alteration of permeability, probably due to direct action on the membrane of sensitive organisms.

Amphotericin B↗
PubMed1962

Effect of polyene antibiotics on protoplasts of Neurospora crassa.

Kinsky, Stephen C. (Washington University, St. Louis, Mo.). Effect of polyene antibiotics on protoplasts of Neurospora crassa. J. Bacteriol. 83:351-358. 1962.-The polyene antibiotics nystatin, amphotericin B, and filipin induced shrinkage of Neurospora crassa protoplasts stabilized in sucrose. At low concentrations of filipin (5 mug per ml), or higher concentrations of nystatin and amphotericin B (20 mug per ml), shrinkage was followed by swelling and lysis (bursting) of protoplasts. The effect of various parameters, such as metabolic inhibitors, protoplast concentration, and polyene concentration, was determined. The available evidence is consistent with the hypothesis that polyene antibiotics act by altering cellular permeability, possibly by reaction with the cell membrane, of sensitive organisms.

Anti-Bacterial Agents↗
PubMed1963

INHIBITION OF THE PLEUROPNEUMONIA-LIKE ORGANISM MYCOPLASMA GALLISEPTICUM BY CERTAIN POLYENE ANTIFUNGAL ANTIBIOTICS.

Lampen, J. Oliver (Rutgers, The State University, New Brunswick, N.J.), James W. Gill, Peter M. Arnow, and I. Magana-Plaza. Inhibition of the pleuropneumonia-like organism Mycoplasma gallisepticum by certain polyene antifungal antibiotics. J. Bacteriol. 86:945-949. 1963.-The growth of Mycoplasma gallisepticum, a sterol-requiring pleuropneumonia-like organism (PPLO), was inhibited by certain polyene antifungal antibiotics at the following concentrations: filipin, 0.5 mug/ml; amphotericin B, 3 mug/ml; and fungichromin, 10 mug/ml. The inhibition of the organism was due to fungicidal action of the polyenes rather than to decreased availability of the sterol. The PPLO rapidly bound nystatin (NY), but was relatively insensitive to this antifungal agent or to N-acetyl-candidin (NAC). Even with a comparatively small inoculum, 100 mug of NY per ml or 50 mug of NAC per ml, were required to inhibit growth. In contrast, Saccharomyces cerevisiae, growing under similar conditions, was completely inhibited by 3 mug of NY or NAC per ml. Filipin, however, was effective against both organisms, inhibiting PPLO and yeast at 0.5 mug/ml and 3 mug/ml, respectively. The relative insensitivity of PPLO to NY was not the result of protection by the sterol present in the growth medium. These organisms, incubated for 2 hr in sterol-free buffer in the presence of 20 mug of NY per ml showed little, if any, inhibition of growth when transferred to growth medium. Under the same conditions, more than 99% of a yeast suspension was killed. It is suggested that the PPLO are primarily sensitive to the disruptive action on the cell membrane which is characteristic of the smaller polyenes (34 to 37 carbon atoms).

Amphotericin B↗
PubMed1965

EFFECT OF CHOLESTEROL ON THE SENSITIVITY OF MYCOPLASMA LAIDLAWII TO THE POLYENE ANTIBIOTIC FILIPIN.

Weber, Morton M. (St. Louis University School of Medicine, St. Louis, Mo.), and Stephen C. Kinsky. Effect of cholesterol on the sensitivity of Mycoplasma laidlawii to the polyene antibiotic filipin. J. Bacteriol. 89:306-312. 1965.-The polyene antibiotic, filipin, inhibited growth and caused lysis of Mycoplasma laidlawii cells which had been cultured in the presence of cholesterol. The antibiotic did not inhibit growth and did not promote lysis of the organism when grown in the absence of cholesterol. These results constitute strong support for the contention that the presence of sterol in the cell membrane is a necessary prerequisite for polyene sensitivity. Higher concentrations of filipin were required to inhibit growth when serum was added to the assay medium than when it was absent. These results suggest binding of the antibiotic to some component in the serum and may partially account for the previous inability to demonstrate growth inhibition by low concentrations of the polyene antibiotics. The extent of growth inhibition due to filipin decreased upon prolonged incubation. Subculture in the presence of high concentrations of antibiotic indicated that the apparent reversal of inhibition was caused by emergence of a filipin-resistant cell population. It was also observed that cells, which originally were rapidly lysed by filipin and digitonin, were no longer responsive to the action of these agents upon incubation in sterol-free medium at 25 or 37 C for several hours. This effect could be prevented by keeping the cells at 2 C. These results may indicate that filipin-resistant cells carry out a metabolic conversion of membrane-localized sterol to a form which can no longer react with the antibiotic. Other possible causes of resistance, which cannot be excluded on the basis of the present data, are discussed.

Acholeplasma laidlawii↗
PubMed2003

Polyene macrolide antibiotics and their applications in human therapy.

Fungal infections represent a serious problem for patients with immune systems compromized either by HIV infection, or administration of immunosuppressive drugs during cancer therapy and organ transplantation. High dissemination and proliferation rates of many pathogenic fungi along with their insusceptibility to common antimicrobial drugs urge implementation of efficient and reliable antifungal therapy. Up to date, polyene macrolide antibiotics proved to be the most effective antifungal agents due to their potent fungicidal activity, broad spectrum, and relatively low frequency of resistance among the fungal pathogens. However, polyene macrolides are rather toxic, causing such serious side effects as renal failure, hypokalemia and thrombophlebitis, especially upon intravenous administration. Current views on the biosynthesis of polyene macrolides, their mode of action and structure-function relationship, as well as strategies used to overcome the toxicity problem are discussed in this review. In addition, some of the new potential applications for polyene macrolides in therapy of prion diseases, HIV infection and cancer are highlighted.

Animals↗
PubMedDate not supplied

Development of liposomal polyene antibiotics: an historical perspective.

PURPOSE: The purpose of this review article is to review the development of a number of liposomal polyene antibiotics. BACKGROUND: In the past thirty years, the increase in life-threatening pre-systemic and systemic fungal infections within cancer, diabetic and AIDS patients have reached alarming proportions. A number of antifungal agents have been developed to combat this problem. In particular, polyene antibiotics such as Amphotericin B (AmB) and Nystatin (Nys) have remained the most effective and widely used agents in the treatment of these infections. However, their administration is limited by dose-dependent toxicities. One such dose-limiting toxicity is renal toxicity. Polyene antibiotic-induced renal toxicity is believed to be mediated by the drug anchoring to cholesterol within the mammalian cell membrane, resulting in pore formation, abnormal electrolyte flux, decrease in adenosine triphosphate (ATP), and eventually a loss of cell viability. CONCLUSION: In the 1980s and 90s a number of promising lipid-based AmB and Nys formulations were developed to overcome these toxicities. This article will review the development of these liposomal polyene antibiotics.

Adenosine Triphosphate↗
PubMed1984

Potentiation of cytotoxicity of anticancer agents by several different polyene antibiotics.

The ability of several different polyenes to potentiate the cytotoxicity of carmustine, lomustine (LOM), and doxorubicin (DX) against AKR mouse leukemia was quantitated. All polyenes could potentiate the cytotoxicity of the anticancer agents; however, the methyl ester derivatives of the heptaenes amphotericin B and candicidin and the triene trienine were most effective with potentiations in the order of ten thousandfold for DX and LOM. A steep dose-response relationship for the polyenes was also noted. Neither the toxicity of the polyenes nor their level of potentiation could be correlated with structure or class.

Animals↗
PubMedDate not supplied

[Effect of polyene antibiotics on bacterial protoplasts].

The carbonyl-conjugated pentaenes flavofungin, nigrofungin and flavopentin exhibit considerable lytic activity toward Micrococcus lysodeikticus and Bacillus megaterium protoplasts. The antibiotics at concentrations of 5 to 14 microgram/ml cause lysis of 50% of the protoplasts within 15 min of their incubation. The antibiotics inhibit the activity of NADH oxidase and malate oxidase by 50% in the lysates of Micrococcus lysodeikticus and Bacillus megaterium protoplasts at concentrations of 30 to 50 microgram/ml; preincubation of the lysates with the antibiotics intensify the inhibiting action of the polyenes. Growth of the bacteria is inhibited when the minimal concentration of the polyenes is 75 to 100 microgram/ml. Interaction of the polyenes with bacterial membranes lacking sterols indicates that resistance of at least some bacteria to polyenes is caused by impermeability of the cell wall for these substances rather than by the absence of sterols in the membranes.

Anti-Bacterial Agents↗
PubMed1978

[Role of sterol structure in complex formation with polyene antibiotics].

The capacity of sterols of different structure being components of artificial bilayer lipid membranes for formation of complexes with polyenic antibiotics, such as amphotericin B, nistatin and levorin was studied. It was shown that sterols delat 5,7-dienic systemin ring B, ergosterol and cholesta-5,7,22-trien 3 beta-ol had the highest affinity to all the 3 antibiotics, while sterols with one double bond in ring B, i. e. cholesterol and brassicasterol had less affinity and sterol without any double bonds in the molecule i.e. 5alpha cholestan 3beta-ol had the least affinity. It was supposed that delta 5,7-sterols had the highest affinity to polyens because of the fact that atoms C-5, C-6; C-7 and C-8 in ring B were practically situated in one plane in contrast to sterols with completely saturated ring B situated in the "conformation chair". Because of this interaction between delta 5,7-sterol ring B and the same flat polyenic site of the antibiotic molecule is sterically most firm since maximum contact is possible between two planes. It was noted that affinity of sterol to the polyenic antibiotics was higher if there were a double bond at 22-23 and methyl group at C-24 in the sterol side chain.

Anti-Bacterial Agents↗
PubMed1980

[Surface activity of polyene antibiotics].

The surface activity properties of polyenic antibiotics, such as amphotericin B, mycoheptin, levorin and nystatin were studied. The critical concentrations for the mycella formation were determined and the values of the polyenic antibiotic surface activity at various temperatures were estimated. It was found that the process of the mycella formation of polyenic antibiotics was defined by a positive change in the entropy. A thermodynamic analysis of the process of the mycella formation of the polyenic antibiotics in aqueous solutions was performed.

Antifungal Agents↗
PubMed1979

Control of permeation of bleomycin A2 by polyene antibiotics in cultured Chinese hamster cells.

Control of permeation of bleomycin A2, a well-known antitumor antibiotic, in combination with various polyene macrolide antibiotics was analyzed in cultured Chinese hamster cells in vitro. Three polyene antibiotics, filipin, pentamycin, and pimaricin, were found to enhance the action of bleomycin A2 remarkably, while amphotericin B or nystatin could not. Although DNA synthesis and colony-forming activity of polyene-sensitive Chinese hamster V79 cells were synergistically inhibited by the combination of filipin and bleomycin A2, in a polyene-resistant subline (AMBR-1) derived from V79, they were only slightly affected in the presence of both drugs. The cellular uptake of [14C]bleomycin A2 by V79 was enhanced 2- to 4-fold in the presence of increasing doses of filipin or pentamycin, but not in the presence of amphotericin B. The treatment of V79 cells with filipin for 20 to 30 min was enought to block DNA synthesis almost completely when combined with 20 microgram belomycin A2 per ml. The pretreatment of the hamster cells with 6 microgram filipin per ml for 60 min continued to enhance the inhibitory action by bleomycin A2 of DNA synthesis up to 5 hr after the removal of filipin from the cultured medium.

Amphotericin B↗
PubMed1981

Inhibition of DNA synthesis and cell cycle in Chinese hamster cells by sterol-binding polyene amphotericin B.

Amphotericin B, a sterol-binding polyene antibiotic, was found to inhibit DNA synthesis more than protein or RNA synthesis of asynchronous cultures of Chinese hamster V79 cells. DNA synthesis in the asynchronous V79 cells was inhibited to 40--60% of the control activity in the presence of 50 micrograms/ml amphotericin B. However, addition of 50 micrograms/ml of polyene immediately after to onset of DNA synthesis (early S phase) caused a drastic reduction of DNA synthesis (below 10--20% of the control in synchronized V79 cells, whereas the inhibition was much lessened when the polyene was added 1 h later (middle S phase). In contrast, there was no inhibition of DNA synthesis by amphotericin B in an amphotericin-B-resistant (AMBR) clone that was derived from V79. Flow microfluorometry analysis confirmed that a large number of asynchronous V79 cells were arrested in the G1 phase of the cell cycle when treated with lower dose of amphotericin B. A higher dose of the polyene antibiotic also accumulated cells at the G2 (or at both S and G2) phase as well as the G1 phase. Morphological studies by scanning electron microscope showed an increased number of V79 cells with decreased microvilli in V79 cells treated with amphotericin B.

Amphotericin B↗
PubMed2004

Linear polyenes: models for the spectroscopy and photophysics of carotenoids.

We have developed procedures for synthesizing dimethyl polyenes using living polymerization techniques and have initiated investigations of the spectroscopic properties of these molecules. Purification using high-performance liquid chromatography (HPLC) of the polyene mixtures resulting from the syntheses promises to provide all-trans polyenes with a wide range in the number of conjugated double bonds. Low temperature optical measurements on these model systems, both in glasses and in n-alkane mixed crystals, yield absorption and fluorescence spectra with considerably higher vibronic resolution than the spectra currently available for carotenoids with comparable conjugation lengths. The dimethyl polyenes thus allow a more precise exploration of the electronic properties of long, linearly conjugated systems. These studies can be used to verify the existence of low-lying singlet states predicted by theory and recently invoked to explain low-resolution fluorescence, Raman excitation spectra, and the transient absorption spectroscopy of carotenoids. Steady state and time-resolved optical studies of the dimethyl series will be used to better understand the energies and dynamics of the low energy electronic states relevant to the photochemistry and photobiology of all linearly conjugated systems.

Carotenoids↗
PubMed2003

Influence of antifungal polyenes on the adhesion of Candida albicans and Candida glabrata to human epithelial cells in vitro.

Candidal adherence to mucosal surfaces is considered as the first step in the pathogenesis of oral candidiasis. We examined the effect of antifungal polyenes, amphotericin B, nystatin and natamycin, at sublethal and minimum inhibitory concentrations (MICs) on the adherence of Candida albicans and Candida glabrata to HeLa cervical carcinoma and HSC-3 oral squamous cell carcinoma cells. A total of six oral Candida isolates were used throughout the study. Two Candida strains, C. albicans (44990) and C. glabrata (MYA-275) were obtained from ATCC. Four Candida strains, C. albicans 19 and 24 and C. glabrata 15 and 21, were isolated from patients with documented Candida-associated denture stomatitis. Cells were either incubated with Candida in the presence of the drug, or pre-incubated with yeasts and exposed subsequently to the drug. In the drug-free controls, the mean number of C. albicans yeasts associated with HeLa cells obtained from all experiments (130.1+/-10.1 yeasts/mm(2)) was significantly greater than that for HSC-3 cells (114.7+/-10.1 yeasts/mm(2); P<0.025). For C. glabrata, the mean adherence to HeLa and HSC-3 cells was 84.4+/-5.5 and 84.4+/-3.3 yeasts/mm(2), respectively, and these values were not statistically different (P>0.4). Candidal adherence was significantly reduced when the tested polyenes were present during the "adherence phase". The obtained values were significantly different from the controls, except for the effect of nystatin at the MIC on the adherence of C. glabrata strain MYA-275 to HeLa cells (P<0.375). Amphotericin B had the highest effect against both Candida species, reducing adherence by approximately 50 and approximately 60%, at the MIC and sublethal concentrations, respectively. The susceptibility of cell-associated Candida to polyenes was decreased markedly and the treatment did not result in significant detachment of adherent yeasts. The reduction in adherence was between 2 and 10%, when compared to the drug-free controls. These findings suggest that sub-therapeutic levels of polyenes that are likely to persist in the oral cavity following topical treatment may modulate candidal colonization when present during the "adherence phase".

Amphotericin B↗
PubMed1998

Spectroscopy features of the binding of polyene antibiotics to human serum albumin.

The alteration in the fluorescence spectra observed for the polyene antibiotics nystatin and amphotericin B in the presence of human serum albumin is due to a decrease in the polar character of the antibiotic environment when these are bound to the protein. Amphotericin B showed two types of binding sites, the first having a very high affinity (5.8 x 10(7) M(-1)) and a secondary binding site with an affinity two orders lower than the primary site. This secondary binding site was very sensitive to temperature change. Nystatin yielded only one type of binding site with an affinity of 1.1 x 10(5) M(-1). Nystatin was found to be bound to fatty acid binding sites in albumin, while amphotericin B was not, suggesting that the fatty acid binding sites are not simple, depending on the number of unsaturated bonds on the polyene antibiotic molecule. Both polyene antibiotics displaced bilirubin bound to albumin, which is in agreement with the similarities of the affinity values of this chromophore and the polyene antibiotics with albumin.

Amphotericin B↗