The lipid composition and permeability to azole of an azole- and polyene-resistant mutant ofCandida albicans

Abstract

Candida albicans 6.4, which is resistant to both polyene and azole groups of antifungal antibiotics, has a larger lipid content and lower polar lipid to neutral lipid ratio compared with other strains that are sensitive or resistant only to azoles. C. albicans 6.4 contains a relatively greater proportion of triacylglycerol in its neutral lipid in the exponential phase of batch culture compared with other strains, but, unlike them, does not accumulate triacylglycerols or any other stored lipid in the stationary phase. Like other strains, in C. albicans 6.4 the major phospholipids are phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol, but sphingomyelin is absent; the major fatty acids are palmitic, palmitoleic, oleic and linoleic acids. In common with other C. albicans strains, strain 6.4 contains non-specific (lyso)phospholipase activity. The main distinctive feature of the lipid composition of C. albicans 6.4 is the absence of ergosterol, which is replaced by methylated sterol; mainly lanosterol, 24-methylene-24,25-dihydrolanosterol and 4-methylergostadiene-3-ol. It is suggested that the altered membrane sterol pattern provides a common basis for the double resistance by preventing polyene binding and reducing azole permeability.Polyenes and azoles (N-substituted imidazoles and triazoles) are clinically the most important antifungal antibiotics for the treatment of candidosis [ 14,19]. The modes of action of polyenes and azoles are related in that both types disrupt membrane properties such as permeability by interfering with lipid components, especially sterols. Polyenes bind directly to sterols causing the leakage of essential ions and low molecular weight metabolites [8,9]. Azoles appear to have several effects on membrane lipid synthesis, but their primary action is probably inhibition of synthesis of ergosterol leading to accumulation of methylated sterol precursors which disrupt membrane functions; at higher concentrations azoles may also interact directly with membrane lipids [for reviews see refs 5 and 21 ].There are differences between the actions of different azoles, and several aspects remain unclear. One approach to resolving this uncertainty is by the use of mutants.Clinical isolates of C. albicans resistant to polyenes are rare, but a number of mutants

Amphotericin B resistance of Aspergillus terreus in a murine model of disseminated aspergillosis

“…A similar ergosterol content has been described in a strain of A. fumigatus which is susceptible to amphotericin B in vivo [23,24]. Polyene antifungal resistance has previously been attributed to lesions in the ergosterol biosynthetic pathway in clinical isolates of Candida albicans [22,25,26] and Cryptococcus neoformans [27] and in laboratory mutants of C. albicans [22,28], A. fennelliae [29] and of a protozoan, Leishmania donovani [30]. Nevertheless, amphotericin B resistance has also been reported in C. albicans [31], Cr.…”

Lipidomics of Candida albicans biofilms reveals phase-dependent production of phospholipid molecular classes and role for lipid rafts in biofilm formation

“…PI has been shown to contribute to antifungal resistance (Abu-Elteen & Whittaker, 1997-1998Hitchcock et al, 1987), biosynthesis and localization of GPI-anchored proteins, germination (Koul et al, 1995) and host pathogenesis (Reynolds, 2009). Additionally, PI metabolism is intricately tied to biosynthesis of yeast sphingolipids, which are a major constituent of membrane-localized lipid rafts.…”

“…Recent studies have revealed that biofilm formation by C. albicans is associated with differential expression of genes and proteins involved in the synthesis of membrane lipids (Lattif et al, 2008;Yeater et al, 2007), and that alteration in the sterol composition is linked to increased azole resistance of C. albicans biofilms (Mukherjee et al, 2003). Additionally, phosphatidylinositol (PI), a key yeast phospholipid, has been shown to contribute to antifungal resistance (Abu-Elteen & Whittaker, 1997-1998Hitchcock et al, 1987) and pathogenesis (Reynolds, 2009). PI is a precursor for the biosynthesis of glycosylinositol phosphorylceramides (GIPCs), the yeast-specific sphingolipid constituents of membrane-localized lipid rafts.…”

In vitro activity of a new antifungal triazole, D0870, against Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus

“…Thus far, two mechanisms for the reduced susceptibility of C. albicans to azole antifungal agents have been described. One is due to changes in the membrane sterol composition which cause a reduced level of permeability of the C. albicans membrane to the drugs; the second is due to a mutation of sterol 14a-demethylase, a cytochrome P450 enzyme, that results in decreased binding affinity for the azole drugs (6,7,14,16 …”