cDNA microarray analysis of the expression profiles of Trichophyton rubrum in response to novel synthetic fatty acid synthase inhibitor PHS11A

Zhang, Wenliang; Yu, Lu; Leng, Wenchuan; Wang, Xiaokui; Wang, Lingling; Deng, Xuming; Yang, Jian; Liu, Tao; Peng, Junping; Wang, Jin; Li, Song; Jin, Qi

doi:10.1016/j.fgb.2007.03.002

Cited by 19 publications

(16 citation statements)

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“…Approximately 300 unigenes were identified in these experiments and only 70 of these were exclusive to drug challenge (Additional file 2). Drug exposure induced the transcription of several multidrug resistance genes, as previously reported in studies in which T. rubrum was exposed to sub-inhibitory levels of KTC, AMB, or other drugs [21,22]. One of these genes [GenBank: FE526598] encodes a putative multidrug resistance protein (MDR) that accumulates in the mycelia when the organism is independently exposed to various cytotoxic agents.…”

Section: Resultsmentioning

confidence: 82%

Transcriptional profiling reveals the expression of novel genes in response to various stimuli in the human dermatophyte Trichophyton rubrum

et al. 2010

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BackgroundCutaneous mycoses are common human infections among healthy and immunocompromised hosts, and the anthropophilic fungus Trichophyton rubrum is the most prevalent microorganism isolated from such clinical cases worldwide. The aim of this study was to determine the transcriptional profile of T. rubrum exposed to various stimuli in order to obtain insights into the responses of this pathogen to different environmental challenges. Therefore, we generated an expressed sequence tag (EST) collection by constructing one cDNA library and nine suppression subtractive hybridization libraries.ResultsThe 1388 unigenes identified in this study were functionally classified based on the Munich Information Center for Protein Sequences (MIPS) categories. The identified proteins were involved in transcriptional regulation, cellular defense and stress, protein degradation, signaling, transport, and secretion, among other functions. Analysis of these unigenes revealed 575 T. rubrum sequences that had not been previously deposited in public databases.ConclusionIn this study, we identified novel T. rubrum genes that will be useful for ORF prediction in genome sequencing and facilitating functional genome analysis. Annotation of these expressed genes revealed metabolic adaptations of T. rubrum to carbon sources, ambient pH shifts, and various antifungal drugs used in medical practice. Furthermore, challenging T. rubrum with cytotoxic drugs and ambient pH shifts extended our understanding of the molecular events possibly involved in the infectious process and resistance to antifungal drugs.

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Section: Resultsmentioning

confidence: 82%

Transcriptional profiling reveals the expression of novel genes in response to various stimuli in the human dermatophyte Trichophyton rubrum

et al. 2010

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“…The microarrays have also been used in comparative genomic hybridization analysis with 22 strains of dermatophytes, including T. rubrum, T. tonsurans, Microsporum canis, and Microsporum gypseum (57)-four out of five species that are currently being sequenced. The microarrays have also been used to investigate expression profiles in response to new antifungal drugs (60,62), an important use of the technology against these important fungi. At the present time, additional transcriptome analyses using the microarrays are being performed to analyze the dermatophyte response to additional antifungals, and the dermatophyte response under conditions that simulate skin infections (Qi Jin, personal communication).…”

Section: Tools For Hypothesis Generation In the Dermatophytesmentioning

confidence: 99%

Generating and Testing Molecular Hypotheses in the Dermatophytes

et al. 2008

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4Dermatophytes are the most common cause of fungal infections worldwide, impacting millions of individuals annually. In the United States alone, this translates into an economic impact on the health care system estimated to exceed $400 million a year for treatment alone (8,46). A recent survey conducted in 16 European countries has shown that more than one-third (35 to 40%) of the 90,000 participants were suffering with a fungal foot disease, mainly caused by dermatophytes (4). In a recent study, 22 to 50% of children in a U.S. day care center exhibited symptoms of dermatophytic scalp infections (2). Despite the prominence of dermatophyte infections and their resulting socioeconomic consequences, the research and medical communities lack a sophisticated understanding of these organisms' biology. Consequently, effective preventatives and therapeutics are lacking. These deficiencies are in large part due to the lack of genetic tools available for the study of these fungi and their host specificities. Several research efforts are now poised to produce genomic and molecular resources that will enable the molecular characterization of dermatophytes. These resources will soon be available for use by the larger research community to address many questions about the biology and pathogenesis of dermatophytes. This review will elaborate on the current status of these resources and their importance to the study of the dermatophytes. DERMATOPHYTE BIOLOGY AND DISEASEDisease. Tinea is a fungal infection of the skin, hair, or nails (reviewed in reference 34). The phrase is made specific by the addition of another term referring to a specific body location. Thus, the term "tinea pedis" refers to a fungal infection of the feet. Other tinea infections include tinea capitis (scalp or head), tinea corporis (body or trunk), and tinea unguium (nails, also known as onychomycosis). These terms do not indicate the infecting organism but the type of infection and the body location. Tinea infections are usually localized to the surface and are rarely systemic or disseminated.Fungal infections can be asymptomatic, they can be acute and severe, associated with inflammation, or they can be chronic (most common) (34). Tinea pedis usually occurs in the toe webs, with considerable scaling, fissuring, maceration, and erythema, accompanied by severe itching or burning. Tinea pedis can also localize to the sole of the foot, extending up the sides of the foot. The destruction of the skin barrier can result in bacterial superinfection. Nail infections are associated with thickening, discoloration, and pain. Scalp infections can cause irreversible hair loss.Organisms. All of the dermatophytes are ascomycetous molds, members of the class Euascomycetes that also includes Aspergillus species and the dimorphic fungi ( Fig. 1) (34). The dermatophytes are classified into three genera: Trichophyton, Microsporum, and Epidermophton. As can be seen in Fig. 2, the dermatophytes are a monophyletic clade, although the assigned genus designations within the clade ...

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“…The expression of T. rubrum FAS1 (fatty acid synthases) and ERG 6 (ergosterol synthesis) genes is modulated by the synthetic FAS inhibitors PHS11A [13] and PHS11B [14]. In this study, we also observed that the inhibition of fatty acid and ergosterol synthesis by quercetin and trans-chalcone may involve transcriptional modulation of these genes since they are down-regulated by both flavonoids .…”

Section: Discussionmentioning

confidence: 56%

“…Ergosterol is a vital component of the fungal cell, but little is known about the genetics and biochemistry of the ergosterol biosynthesis pathway and only 20 genes involved in the biosynthesis of ergosterol in T. rubrum have been sequenced [24]. Zhang et al [13] demonstrated up-regulation of the FAS1 , FAS2 and ERG6 genes in response to PHS11A. In addition, the ERG5 , ERG6 and ERG25 genes have been shown to be up-regulated in Candida albicans strain SC5314-AR, which is resistant to fluconazole and amphotericin B.…”

Section: Discussionmentioning

confidence: 99%

“…DNA microarray studies using T. rubrum and synthetic inhibitors of FAS (PHS11A and PHS11B) have shown marked transcriptional modulation of several genes such as FAS1 and FAS2 , ERG6 (a gene involved in ergosterol metabolism), and multidrug resistance genes [13,14]. We evaluated the antifungal activity of flavonoids against T. rubrum and their effects on fatty acid and ergosterol synthesis using a wild-type strain and a mutant strain (Δ TruMDR2 ) that carries a disrupted version of an ABC transporter involved in multidrug resistance [15].…”

Section: Introductionmentioning

confidence: 99%

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Trans-chalcone and quercetin down-regulate fatty acid synthase gene expression and reduce ergosterol content in the human pathogenic dermatophyte Trichophyton rubrum

Bitencourt

Komoto

Massaroto

et al. 2013

BMC Complement Altern Med

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BackgroundFatty acid synthase (FAS) is a promising antifungal target due to its marked structural differences between fungal and mammalian cells. The aim of this study was to evaluate the antifungal activity of flavonoids described in the scientific literature as FAS inhibitors (quercetin, trans-chalcone, ellagic acid, luteolin, galangin, and genistein) against the dermatophyte Trichophyton rubrum and their effects on fatty acid and ergosterol synthesis.MethodsThe antifungal activity of the natural products was tested by the microdilution assay for determination of the minimum inhibitory concentration (MIC). The effect of the compounds on the cell membrane was evaluated using a protoplast regeneration assay. Ergosterol content was quantified by spectrophotometry. Inhibition of FAS by flavonoids was evaluated by an enzymatic assay to determine IC50 values. Quantitative RT-PCR was used to measure transcription levels of the FAS1 and ERG6 genes involved in fatty acid and ergosterol biosynthesis, respectively, during exposure of T. rubrum to the flavonoids tested.ResultsThe flavonoids quercetin and trans-chalcone were effective against T. rubrum, with MICs of 125 and 7.5 μg/mL for the wild-type strain (MYA3108) and of 63 and 1.9 μg/mL for the ABC transporter mutant strain (ΔTruMDR2), respectively. The MICs of the fluconazole and cerulenin controls were 63 and 125 μg/mL for the wild-type strain and 30 and 15 μg/mL for the mutant strain, respectively. Quercetin and trans-chalcone also reduced ergosterol content in the two strains, indicating that interference with fatty acid and ergosterol synthesis caused cell membrane disruption. The MIC of quercetin reduced the number of regenerated protoplasts by 30.26% (wild-type strain) and by 91.66% (mutant strain). Half the MIC (0.5 MIC) of quercetin did not reduce the number of regenerated wild-type fungal colonies, but caused a 36.19% reduction in the number of mutant strain protoplasts. In contrast, the MIC and 0.5 MIC of trans-chalcone and cerulenin drastically reduced protoplast regeneration in the two strains. The FAS1 gene was repressed in the presence of MICs of quercetin, trans-chalcone, fluconazole and cerulenin. The ERG6 gene was induced in the presence of MICs of fluconazole and cerulenin and was repressed in the presence of MICs of trans-chalcone and quercetin. Trans-chalcone and quercetin inhibited the enzymatic activity of FAS, with IC50 values of 68.23 and 17.1 μg/mL, respectively.ConclusionTrans-chalcone and quercetin showed antifungal activity against T. rubrum, reducing ergosterol levels and modulating the expression of FAS1 and ERG6.

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cDNA microarray analysis of the expression profiles of Trichophyton rubrum in response to novel synthetic fatty acid synthase inhibitor PHS11A

Cited by 19 publications

References 44 publications

Transcriptional profiling reveals the expression of novel genes in response to various stimuli in the human dermatophyte Trichophyton rubrum

Transcriptional profiling reveals the expression of novel genes in response to various stimuli in the human dermatophyte Trichophyton rubrum

Generating and Testing Molecular Hypotheses in the Dermatophytes

Trans-chalcone and quercetin down-regulate fatty acid synthase gene expression and reduce ergosterol content in the human pathogenic dermatophyte Trichophyton rubrum

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