Sterol and Fatty Acid Composition of<i>Candida lusitaniae</i>Clinical Isolates

Peyron, F; Favel, Anne; Calaf, R; Michel-Nguyen, A.; Bonaly, R.; Coulon, Joël

doi:10.1128/aac.46.2.531-533.2002

Cited by 16 publications

(9 citation statements)

References 19 publications

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“…Although the sterol composition of C. albicans has been studied before (44)(45)(46), a more detailed analysis of the amounts and identities of minor sterols has not been carried out. The wild-type cells contained a sterol composition typical of ascomycetous fungi (47), with many of the same sterols reported by other investigators for C. albicans.…”

Section: Resultsmentioning

confidence: 99%

Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C‐25 in the sterol side chain

Kanagasabai

Zhou

Liu

et al. 2004

Lipids

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The sterol substrate analog 25-thialanosterol and its corresponding sulfonium salt were evaluated for their ability to serve as antifungal agents and to inhibit sterol methyltransferase (SMT) activity in Candida albicans. Both compounds inhibited cell proliferation, were fungistatic, interrupted the yeast-like-form to germ-tube-form transition, and resulted in the accumulation of zymosterol and related delta24-sterols concurrent with a decrease in ergosterol, as was expected for the specific inhibition of SMT activity. Feedback on sterol synthesis was evidenced by elevated levels of cellular sterols in treated vs. control cultures. However, neither farnesol nor squalene accumulated in significant amounts in treated cultures, suggesting that carbon flux is channeled from the isoprenoid pathway to the sterol pathway with minor interruption or redirection until blockage at the C-methylation step. Activity assays using solubilized C. albicans SMT confirmed the inhibitors impair SMT action. Kinetic analysis indicated that 25-thialanosterol inhibited SMT with the properties of a time-dependent mechanism-based inactivator Ki of 5 microM and apparent kinact of 0.013 min(-1), whereas the corresponding sulfonium salt was a reversible-type transition state analog exhibiting a Ki of 20 nM. The results are interpreted to imply changes in ergosterol homeostasis as influenced by SMT activity can control growth and the morphological transition in C. albicans, possibly affecting disease development.

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Section: Resultsmentioning

confidence: 99%

Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C‐25 in the sterol side chain

Kanagasabai

Zhou

Liu

et al. 2004

Lipids

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“…Although this phenomenon has been known and noted for more than 25 years (24), the genetic mechanism(s) for this acquired resistance is not well understood. There are data supporting the presence of gene mutations in the ergosterol biosynthetic pathway, thereby blocking production of the binding target, i.e., ergosterol (4,17). A mutation mechanism(s) is credible since C. lusitaniae is a haploid yeast and nonlethal mutations can have a direct effect on gene expression.…”

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confidence: 99%

Phenotypic Switching in Candida lusitaniae on Copper Sulfate Indicator Agar: Association with Amphotericin B Resistance and Filamentation

2006

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Candida lusitaniae is an opportunistic yeast pathogen that has the ability to develop resistance to amphotericin B (AmB). The mechanism(s) for this resistance is not well understood, although there are data supporting mutations in sterol pathways and other data supporting phenotypic switching (PS). The goal of this study was to determine whether C. lusitaniae has a PS system and to characterize any phenotypes, including any changes in AmB MICs. When 10 4 CFU of an AmB-resistant (MIC of 16 to 32 g/ml) clinical strain was plated on yeast-peptone-dextrose (YPD) agar with 1 mM CuSO 4 , three colony colors were observed: light brown (LB) Ͼ Ͼ dark brown (DB) > white (W), similar to the result for Candida glabrata. Switching did occur with high AmB resistance (MIC of 256 g/ml) being associated with W, whereas LB and DB colonies had MICs of 2 to 8 g/ml and 2 to 16 g/ml, respectively. Filamentation (pseudohyphae) was associated with DB colonies. All phenotypes occurred spontaneously with greater frequency (ϳ10 ؊2 to 10 ؊4 ) than spontaneous mutations, and all phenotypes were reversible, fulfilling the two PS criteria. High AmB MICs were always associated with W colonies but not with all W colonies. Detection of PS on YPD-CuSO 4 is also similar to that in Candida glabrata, and we hypothesize that this is due to similarities in metallothionein gene expression. Phenotypic switching represents a key strategy in C. lusitaniae that confers a selective advantage during environmental challenges, including the ability to switch to AmB resistance.

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“…One study found a correlation between amphotericin B resistance and sterol composition consistent with a defect in the ⌬8-7 isomerase Erg2 (38,39), which can also result in amphotericin B resistance in C. albicans and C. neoformans (8,27), but overall, there is limited information on the genome of C. lusitaniae, and there have not been any specific attempts to identify genes in the ergosterol biosynthetic pathway.…”

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confidence: 99%

Disruption of Ergosterol Biosynthesis Confers Resistance to Amphotericin B inCandida lusitaniae

Young

Hull²,

Heitman

2003

Antimicrob Agents Chemother

163

120

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Candida lusitaniae is an emerging human pathogen that, unlike other fungal pathogens, frequently develops resistance to the commonly used antifungal agent amphotericin B. Amphotericin B is a member of the polyene class of antifungal drugs, which impair fungal cell membrane integrity. Here we analyzed mechanisms contributing to amphotericin B resistance in C. lusitaniae. Sensitivity to polyenes in the related fungi Saccharomyces cerevisiae and Candida albicans requires the ergosterol biosynthetic gene ERG6. In an effort to understand the mechanisms contributing to amphotericin B resistance in C. lusitaniae, we isolated the ERG6 gene and created a C. lusitaniae erg6⌬ strain. This mutant strain exhibited a growth defect, was resistant to amphotericin B, and was hypersensitive to other sterol inhibitors. Based on the similarities between the phenotypes of the erg6⌬ mutant and clinical isolates of C. lusitaniae resistant to amphotericin B, we analyzed ERG6 expression levels and ergosterol content in multiple clinical isolates. C. lusitaniae amphotericin B-resistant isolates were found to have increased levels of ERG6 transcript as well as reduced ergosterol content. These changes suggest that another gene in the ergosterol biosynthetic pathway could be mutated or misregulated. Further transcript analysis showed that expression of the ERG3 gene, which encodes C-5 sterol desaturase, was reduced in two amphotericin B-resistant isolates. Our findings reveal that mutation or altered expression of ergosterol biosynthetic genes can result in resistance to amphotericin B in C. lusitaniae.

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Sterol and Fatty Acid Composition ofCandida lusitaniaeClinical Isolates

Cited by 16 publications

References 19 publications

Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C‐25 in the sterol side chain

Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C‐25 in the sterol side chain

Phenotypic Switching in Candida lusitaniae on Copper Sulfate Indicator Agar: Association with Amphotericin B Resistance and Filamentation

Disruption of Ergosterol Biosynthesis Confers Resistance to Amphotericin B inCandida lusitaniae

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