Transcriptional Profiles of the Response to Ketoconazole and Amphotericin B in
            <i>Trichophyton rubrum</i>

Yu, Lu; Zhang, Wenliang; Wang, Lingling; Yang, Jian; Liu, Tao; Peng, Junping; Leng, Wenchuan; Chen, Lihong; Li, Ruoyu; Jin, Qi

doi:10.1128/aac.00755-06

Cited by 69 publications

(71 citation statements)

References 37 publications

(33 reference statements)

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“…To further investigate cellular responses to perturbation of ergosterol biosynthesis stimulated by 10b, we detected the expression of sterol metabolism genes by real-time RT-PCR analyses. The results revealed a global upregulation of sterol metabolism genes, including gene ERG24, ERG5, and ERG11, which is consistent with previous reports [22,23] . This was presumed as a result of feedback control [24] .…”

Section: Discussionsupporting

confidence: 81%

2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway

et al. 2009

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Aim: To investigate the action mechanism of a novel chemical structural aminotetralin derivate, 2-Amino-Nonyl-6-Methoxyl-Tetralin Muriate (10b), against Candida albicans (C albicans) in the ergosterol biosynthetic pathway. Methods: Antifungal susceptibility test of 10b was carried out using broth microdilution method, the action mechanism of 10b against C albicans was investigated by GC-MS spectrometry and real-time RT-PCR assay, and cytotoxicity of 10b in vitro was assessed by MTS/ PMS reduction assay. Results: 10b reduced the ergosterol content markedly, and the 50% ergosterol content inhibitory concentration (ECIC 50 value) was 0.08 μg/mL. Although the sterol composition of 10b-grown cells was completely identical with that of erg24 strain, the content of ergosta-8,14,22-trienol in 10b-grown cells was much higher than that in erg24 strain. Real-time RT-PCR assay revealed a global upregulation of sterol metabolism genes. In addition, the 50% inhibitory concentration (IC 50 value) of 10b was 11.30 μg/mL for murine embryonic fibroblasts and 35.70 μg/mL for human normal liver cells. Conclusion: 10b possessed a mode of action different from that of azoles and morpholines, whose targets were sterol C-14 reductase (encoded by ERG24 gene) and sterol C-5 desaturase (encoded by ERG3) related enzyme. Although 10b seemed to reduce MTS/PMS reduction in a dose dependent manner, IC 50 value for mammalian cells was much higher than 50% minimum inhibitory concentration (MIC 50 ) value for C albicans. This indicates that the formulation is preliminarily safe and warrants further study for possible human applications.

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Section: Discussionsupporting

confidence: 81%

2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway

et al. 2009

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“…Dermatophytes grow slowly under laboratory conditions, genetic tools are only poorly developed, and full genome sequence information for these micro-organisms has only become available very recently (http://www.broadinstitute.org/annotation/ genome/microsporum_gypseum/MultiHome.html). Broadscale gene expression analysis in dermatophytes by cDNA microarrays has been used to study the response of Trichophyton rubrum to various antimycotics and fatty acid synthase inhibitors, and in the analysis of different developmental phases (Liu et al, 2007;Yu et al, 2007;Zhang et al, 2007Zhang et al, , 2009. In order to better understand the particular host adaptation mechanisms of dermatophytes it appeared timely to study a broad-scale gene expression profile in these fungi during infection.…”

Section: Introductionmentioning

confidence: 99%

Differential gene expression in the pathogenic dermatophyte Arthroderma benhamiae in vitro versus during infection

et al. 2010

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Although dermatophytes are the most common agents of superficial mycoses in humans and animals, the molecular basis of the pathogenicity of these fungi is largely unknown. In vitro digestion of keratin by dermatophytes is associated with the secretion of multiple proteases, which are assumed to be responsible for their particular specialization to colonize and degrade keratinized host structures during infection. To investigate the role of individual secreted proteases in dermatophytosis, a guinea pig infection model was established for the zoophilic dermatophyte Arthroderma benhamiae, which causes highly inflammatory cutaneous infections in humans and rodents. By use of a cDNA microarray covering approximately 20-25 % of the A. benhamiae genome and containing sequences of at least 23 protease genes, we revealed a distinct in vivo protease gene expression profile in the fungal cells, which was surprisingly different from the pattern elicited during in vitro growth on keratin. Instead of the major in vitroexpressed proteases, others were activated specifically during infection. These enzymes are therefore suggested to fulfil important functions that are not exclusively associated with the degradation of keratin. Most notably, the gene encoding the serine protease subtilisin 6, which is a known major allergen in the related dermatophyte Trichophyton rubrum and putatively linked to host inflammation, was found to be the most strongly upregulated gene during infection. In addition, our approach identified other candidate pathogenicity-related factors in A. benhamiae, such as genes encoding key enzymes of the glyoxylate cycle and an opsin-related protein.Our work provides what we believe to be the first broad-scale gene expression profile in human pathogenic dermatophytes during infection, and points to putative virulence-associated mechanisms that make these micro-organisms the most successful aetiological agents of superficial mycoses.Abbreviations: FDR, false discovery rate; MFS, major facilitator superfamily; PAS, periodic acid Schiff; qRT-PCR, quantitative reverse-transcription PCR.

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“…To survive under antifungal azole stress, fungi adjust the transcriptional levels of a number of genes (20,36,(43)(44)(45). Many of these azole-responsive genes are known to contribute to azole adaptation and resistance (17,20,23,(46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress

Wang

Zhang

Chen

et al. 2015

Antimicrob Agents Chemother

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bAzoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungal drug sensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription of ads-4 in Neurospora crassa cells increased when they were subjected to ketoconazole treatment, whereas the deletion of ads-4 resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression of ads-4 increased resistance to fluconazole and ketoconazole in N. crassa. Transcriptome sequencing (RNA-seq) analysis, followed by quantitative reverse transcription (qRT)-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress in N. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase (ERG5), and a lipid transporter (NcRTA2) that is involved in calcineurin-mediated azole resistance. Deletion of the ads-4-homologous gene Afads-4 in Aspergillus fumigatus caused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of antifungal pesticides and drugs. F ilamentous fungi cause over 70% of plant diseases, and some can cause deadly infections in humans (1-5). Azoles (e.g., itraconazole [ITA], fluconazole [FLC], and ketoconazole [KTC]) are the most commonly used antifungal drugs in medicine, and some azoles, such as triadimenol and propiconazole, are also used to control fungal diseases in plants (6). Antifungal azoles inhibit 14␣-methyl sterol demethylase (encoded by ERG11), a key enzyme involved in fungal ergosterol biosynthesis. This leads to changes in membrane consistency (7,8). In addition to blocking ergosterol production, the inhibition of ERG11 by azoles results in the accumulation of toxic 14␣-methylated sterol intermediates (9, 10).Fungi can adapt to azole stress by rapidly increasing the expression of a number of genes. Increased expression of some azoleresponsive genes, such as genes encoding azole efflux pumps and genes involved in ergosterol biosynthesis, can increase resistance to azoles (11,12). Previous studies in Saccharomyces cerevisiae and Candida albicans identified a number of regulatory genes that mediate azole responses. The transcription factors Pdr1p and Pdr3p in S. cerevisiae and their homologs in C. albicans regulate azole responses by c...

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Transcriptional Profiles of the Response to Ketoconazole and Amphotericin B in Trichophyton rubrum

Cited by 69 publications

References 37 publications

2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway

2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway

Differential gene expression in the pathogenic dermatophyte Arthroderma benhamiae in vitro versus during infection

Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress

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