3 Biological Activity of Polyene Antibiotics

Sm, Hammond

doi:10.1016/s0079-6468(08)70148-6

Cited by 105 publications

(44 citation statements)

References 344 publications

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“…Similar differences in non-esterified sterol have been observed in polyene-resistant strains of C. albicans (Hammond, 1977;Pierce et al, 1978) but no comparative data exist for other azole-resistant strains. The non-esterified sterol in all strains was comprised of ergosterol, with only traces of other components.…”

Section: Neutral Lipid Compositionmentioning

confidence: 74%

The Lipid Composition of Azole-sensitive and Azole-resistant Strains of Candida albicans

Hitchcock¹,

Barrett‐Bee²,

Russell³

1986

Microbiology

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The lipid compositions of two azole-sensitive (A and B2630) and two azole-resistant (AD and KB) strains of the opportunistic fungal pathogen Candida albicans were studied by using several lipid extraction procedures: no differences were observed between the lipid content or total phospholipid/neutral lipid ratios of the four strains. All contained phosphatidylethanolamine, phosp hatidylc holine, phosphatid ylinosi to1 and p hosp hat id ylserine as major phospholipids, with smaller amounts of phosphatidylglycerol and diphosphatidylglycerol ; the relative proportions of these lipids differed between all four strains. The fatty acid composition of each major phospholipid within each strain differed, and there were also interstrain differences. A marked effect of culture growth phase in batch culture on lipid composition was observed. The major neutral lipids in each strain were triacylglycerol, non-esterified sterol and non-esterified fatty acid. The fatty acid compositions of the three fatty-acid-containing neutral lipids were distinct from each other and the phospholipids, and there were also interstrain differences. All strains possessed (1yso)phospholipase activity, which was nonspecific. The proportions of triacylglycerol and non-esterified fatty acid did not vary between strains, but the azole-resistant strains AD and KB contained more non-esterified sterol, giving them a phospholipid/sterol ratio approximately half that of azole-sensitive strains. There appeared to be a relationship between the phospholipid/sterol ratio of exponentially growing sensitive strains and their ability to take up azole; this did not extend to the resistant strains, which either did not take up azole (AD and KB) or took it up at a faster rate (Darlington) than sensitive strains. INTRODUCTIONCandida albicans is a widespread and troublesome opportunistic pathogen that causes a variety of superficial and deep-seated mycoses (Odds, 1979). Of the relatively few antifungal antibiotics available, those most commonly used to treat candidosis are the polyenes and the more recently introduced imidazoles (Speller, 1980). Polyenes work by complexing with membrane sterols (Hamilton-Miller, 1973). The primary action of imidazoles is probably inhibition of ergosterol synthesis that leads to an accumulation of 14a-methyl sterols which disrupt membrane structure and function (Van den Bossche et ul., 1982, 1983). However, imidazole actions are complex: they also inhibit a number of other yeast (and mammalian) membrane-bound enzymes (Uno et al., Mason et al., 1985), and at higher concentrations some of them affect yeast membranes by direct interaction with lipids (Cope, 1980; Brasseur et al., 1983).Clinical isolates of C. albicans vary considerably in their sensitivities to imidazoles (e.g. see Ryley et al., 1984), and azole-resistant strains have been isolated (Holt & Azmi, 1978 ;Horsburgh & Kirkpatrick, 1983; Warnock et al., 1983). The failure of two of these resistant strains (AD and , 1984). This might be due to an altered membrane lipid compos...

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Section: Neutral Lipid Compositionmentioning

confidence: 74%

The Lipid Composition of Azole-sensitive and Azole-resistant Strains of Candida albicans

Hitchcock¹,

Barrett‐Bee²,

Russell³

1986

Microbiology

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“…capri has been studied extensively by Benyoucef et al (3,4). These The pores formed by AmB allow K+leakage but also Na+ intake since they exhibit practically no intercationic selectivity (11). In the presence of an excess of intracellular Na+, the K+ transport system could be stimulated, as already has been observed in AmB-treated 3T3 cells (16) Whatever the transfer mechanism is, the sensitivity to AmB, observed indirectly, is very different for ergosterolcontaining than for cholesterol-containing membranes.…”

mentioning

confidence: 97%

Transfer of amphotericin B from gel state vesicles to mycoplasma cells: biphasic action on potassium transport and permeability

Vertut-Croquin¹,

Bolard²,

Gary-Bobo³

1985

Antimicrob Agents Chemother

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The action of amphotericin B on the K+ permeability of Mycoplasma mycoides var. capr cells, containing either cholesterol or ergosterol in their membranes, was studied. When the drug, solubilized in dimethyl sulfoxide, was added directly to the cell suspension, a slightly greater sensitivity to permeabilization was observed for ergosterol-containing cells, confirming the data reported in the literature. When amphotericin B bound to gel state phospholipid vesicles was added to the cell suspension, two effects on cholesterol-containing cells were observed. First, the K+ active transport rates increased; membrane permeabilization and K+ leakage were subsequently detected. For ergosterol containing cells these sequential events were observed only at amphotericin B concentrations below 10-6 M. At higher concentrations only K+ leakage was observed. The second permeabilization effect varied with the amphotericin B concentration in different ways in the two types of cells. The permeabilization of ergosterol-containing membranes depended on the amphotericin B/phospholipid molar ratio, whereas the permeabilization of cholesterol-containing membranes did not. In general, the latter remained fairly constant when the total amphotericin B concentration in the medium varied.The antibiotic activity of amphotericin B (AmB) is related to the channels this drug forms in cell membranes (for a review, see reference 11). AmB and related compounds are used in antifungal therapy, since ergosterol-containing membranes are more sensitive to their action than cholesterolcontaining ohes (for a review, see reference 15). Although numerous studies have been carried out, leading to the development of elaborate models (9, 17), little is known about the complex process which occurs during the interaction of AmB with membranes and which leads to pore formation.The poor water solubility of AmB, which results in its aggregation in aqueous medium, has been a major impediment in studying this process. The interaction of these aggregates with membranes is difficult to analyze in terms of the successive molecular events involved and thus has been dealt with as an all or nothing process.This impediment can be overcome by making use of the ability of AmB to exchange between membranes: instead of introducing into the cell suspension AmB as a dimethyl formamide or dimethyl sulfoxide (DMSO) solution, which results in its aggregation, AmB is first incorporated into lipid vesicles which are then introduced into the membrane suspension. By this method, which completely eliminates the presence of AmB in its aggregated form, it has been shown that the affinity of AmB for membranes is a function of the physical state of the membrane (6). More recently, a study of the interaction of AmB with cholesterol and ergosterol-containing phospholipid vesicles revealed that the selectivity of AmB for the latter was much greater than the selectivity currently admitted on the basis of the results obtained by direct application to these membranes of the antibiotic dissolved i...

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“…Mycosamine moieties are also found attached to the macrolactone rings of the polyene macrolide antibiotics amphotericin (10), candicidin/FR-008 (11,13), pimaricin (3), and rimocidin (26) which are also important antifungal agents. The mode of action of all these antibiotics is suggested to be the formation of complexes with the membrane sterols of target cells, creating hydrophilic channels (16) allowing the leakage of Na ϩ and K ϩ ions from fungal cells, eventually leading to cell death (18). For amphotericin, it has been found that each complex consists of eight antibiotic molecules, with hydrophilic polyol regions lining the aqueous central channel (4,22).…”

mentioning

confidence: 99%

Analysis of the Mycosamine Biosynthesis and Attachment Genes in the Nystatin Biosynthetic Gene Cluster of Streptomyces noursei ATCC 11455

Nedal

Sletta

Brautaset

et al. 2007

Appl Environ Microbiol

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The polyene macrolide antibiotic nystatin produced by Streptomyces noursei contains a deoxyaminosugar mycosamine moiety attached to the C-19 carbon of the macrolactone ring through the ␤-glycosidic bond. The nystatin biosynthetic gene cluster contains three genes, nysDI, nysDII, and nysDIII, encoding enzymes with presumed roles in mycosamine biosynthesis and attachment as glycosyltransferase, aminotransferase, and GDP-mannose dehydratase, respectively. In the present study, the functions of these three genes were analyzed. The recombinant NysDIII protein was expressed in Escherichia coli and purified, and its in vitro GDP-mannose dehydratase activity was demonstrated. The nysDI and nysDII genes were inactivated individually in S. noursei, and analyses of the resulting mutants showed that both genes produced nystatinolide and 10-deoxynystatinolide as major products. Expression of the nysDI and nysDII genes in trans in the respective mutants partially restored nystatin biosynthesis in both cases, supporting the predicted roles of these two genes in mycosamine biosynthesis and attachment. Both antifungal and hemolytic activities of the purified nystatinolides were shown to be strongly reduced compared to those of nystatin, confirming the importance of the mycosamine moiety for the biological activity of nystatin.

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3 Biological Activity of Polyene Antibiotics

Cited by 105 publications

References 344 publications

The Lipid Composition of Azole-sensitive and Azole-resistant Strains of Candida albicans

The Lipid Composition of Azole-sensitive and Azole-resistant Strains of Candida albicans

Transfer of amphotericin B from gel state vesicles to mycoplasma cells: biphasic action on potassium transport and permeability

Analysis of the Mycosamine Biosynthesis and Attachment Genes in the Nystatin Biosynthetic Gene Cluster of Streptomyces noursei ATCC 11455

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