Functional Analysis of
 cis
 - and
 trans
 -Acting Elements of the
 Candida albicans CDR2
 Promoter with a Novel Promoter Reporter System

Coste, Alix T.; Crittin, Jérôme; Bauser, Christopher A.; Rohde, B; Sanglard, Dominique

doi:10.1128/ec.00069-09

Cited by 74 publications

(80 citation statements)

References 26 publications

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“…Twelve amino acid substitutions were identified in the TAC1 genes of these eight isolates that were not present in the nucleotide sequence of the fluconazole-susceptible P4V2 isolate (Table 5). One of these amino acid substitutions, A736V, has previously been identified as a GOF mutation in the TAC1 gene of clinical C. albicans isolates, leading to upregulation of the CDR-encoded efflux pumps (15). This substitution occurred in the last isolate recovered from patient 11 during a follow-up clinical assessment in 2010 and correlated with significant constitutive upregulation of the CDR1 and CDR2 genes (Table 5).…”

Section: Vol 49 2011 Analysis Of C Albicans From Irish Apeced Patimentioning

confidence: 99%

“…An association between the mating type of C. albicans isolates and azole resistance has previously been observed, due to the proximity of the MAT mating type gene to the TAC1 gene on chromosome 5 (14,50). Gain-of-function (GOF) mutations occurring in the transcriptional activator TAC1 gene have been shown to be responsible for upregulation of CDR-encoded efflux pumps (15,50,56). Similarly, GOF mutations in the MRR1 transcriptional regulator gene have been associated with upregulation of the Mdr1 efflux pump in C. albicans and C. dubliniensis (18,50).…”

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confidence: 99%

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Microbiological Screening of Irish Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Reveals Persistence of Candida albicans Strains, Gradual Reduction in Susceptibility to Azoles, and Incidences of Clinical Signs of Oral Candidiasis without Culture Evidence

et al. 2011

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Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) are prone to chronic mucocutaneous candidiasis, which is often treated with azoles. The purpose of this study was to characterize the oral Candida populations from 16 Irish APECED patients, who comprise approximately half the total number identified in Ireland, and to examine the effect of intermittent antifungal therapy on the azole susceptibility patterns of Candida isolates. Patients attended between one and four clinical evaluations over a 5-year period, providing oral rinses and/or oral swab samples each time. Candida was recovered from 14/16 patients, and Candida albicans was the only Candida species identified. Interestingly, clinical diagnosis of candidiasis did not correlate with microbiological evidence of Candida infection at 7/22 (32%) clinical assessments. Multilocus sequence typing analysis of C. albicans isolates recovered from the same patients on separate occasions identified the same sequence type each time. Fluconazole resistance was detected in isolates from one patient, and isolates exhibiting a progressive reduction in itraconazole and/or fluconazole susceptibility were identified in a further 3/16 patients, in each case correlating with the upregulation of CDR-and MDR-encoded efflux pumps. Mutations were also identified in the ERG11 and the TAC1 genes of isolates from these four patients; some of these mutations have previously been associated with azole resistance. The findings suggest that alternative Candida treatment options, other than azoles such as chlorhexidine, should be considered in APECED patients and that clinical diagnosis of oral candidiasis should be confirmed by culture prior to the commencement of anti-Candida therapy.

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Section: Vol 49 2011 Analysis Of C Albicans From Irish Apeced Patimentioning

confidence: 99%

mentioning

confidence: 99%

Microbiological Screening of Irish Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Reveals Persistence of Candida albicans Strains, Gradual Reduction in Susceptibility to Azoles, and Incidences of Clinical Signs of Oral Candidiasis without Culture Evidence

et al. 2011

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“…In C. albicans, the ABC transporters Cdr1 and Cdr2 and their upregulation are controlled by the transcription factor (TF) TAC1 (for transcriptional activator of CDR genes). So-called gain-of-function (GOF) mutations in TAC1 confer hyperactivity to this transcription factor and result in high expression of CDR1 and CDR2 (12)(13)(14). Mdr1 is a member of the major facilitator family and is a known mediator of azole resistance in C. albicans when upregulated (9).…”

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confidence: 99%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

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Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur in Candida albicans principally by overexpression of multidrug transporter gene CDR1, CDR2, or MDR1 or by overexpression of ERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs) TAC1 (involved in the control of CDR1 and CDR2), MRR1 (involved in the control of MDR1), and UPC2 (involved in the control of ERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to C. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of C. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations on C. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither TAC1 nor MRR1 GOF mutations had a significant effect on C. albicans virulence. In contrast, the presence of two hyperactive UPC2 alleles in C. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with UPC2 hyperactive alleles was observed in competition experiments with the wild type in vivo but not in vitro. Interestingly, UPC2 hyperactivity delayed filamentation of C. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the UPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect of UPC2 on virulence. In conclusion, among the major TFs involved in azole resistance, only UPC2 had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.

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“…We found that Gu5 had acquired a G2939A substitution in TAC1 and become homozygous for the mutation. The resulting G980E exchange in Tac1 has also been found in other fluconazole-resistant isolates and shown to mediate CDR1/CDR2 overexpression and increased drug resistance (12,14). Isolate TW17 has long been known to overexpress MDR1 (25).…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, GOF mutations in Mrr1 cause overexpression of the multidrug efflux pump MDR1 and additional genes that contribute to fluconazole resistance (5)(6)(7)(8)(9)(10)(11). Similarly, GOF mutations in Tac1 confer fluconazole resistance by mediating overexpression of the multidrug efflux pumps CDR1 and CDR2 and other Tac1 target genes (12)(13)(14)(15)(16)(17). Finally, GOF mutations in Upc2 result in upregulation of ERG11 and other ergosterol biosynthesis genes (18)(19)(20)(21).…”

mentioning

confidence: 99%

Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains

Popp

Hampe

Hertlein

et al. 2017

Antimicrob Agents Chemother

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The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis. Resistance is often caused by gain-of-function mutations in the transcription factors Mrr1 and Tac1, which result in constitutive overexpression of multidrug efflux pumps, and Upc2, which result in constitutive overexpression of ergosterol biosynthesis genes. However, the deregulated gene expression that is caused by hyperactive forms of these transcription factors also reduces the fitness of the cells in the absence of the drug. To investigate whether fluconazole-resistant clinical C. albicans isolates have overcome the fitness costs of drug resistance, we assessed the relative fitness of C. albicans isolates containing resistance mutations in these transcription factors in competition with matched drug-susceptible isolates from the same patients. Most of the fluconazole-resistant isolates were outcompeted by the corresponding drug-susceptible isolates when grown in rich medium without fluconazole. On the other hand, some resistant isolates with gain-of-function mutations in MRR1 did not exhibit reduced fitness under these conditions. In a mouse model of disseminated candidiasis, three out of four tested fluconazole-resistant clinical isolates did not exhibit a significant fitness defect. However, all four fluconazole-resistant isolates were outcompeted by the matched susceptible isolates in a mouse model of gastrointestinal colonization, demonstrating that the effects of drug resistance on in vivo fitness depend on the host niche. Collectively, our results indicate that the fitness costs of drug resistance in C. albicans are not easily remediated, especially when proper control of gene expression is required for successful adaptation to life within a mammalian host.

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Functional Analysis of cis - and trans -Acting Elements of the Candida albicans CDR2 Promoter with a Novel Promoter Reporter System

Cited by 74 publications

References 26 publications

Microbiological Screening of Irish Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Reveals Persistence of Candida albicans Strains, Gradual Reduction in Susceptibility to Azoles, and Incidences of Clinical Signs of Oral Candidiasis without Culture Evidence

Microbiological Screening of Irish Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Reveals Persistence of Candida albicans Strains, Gradual Reduction in Susceptibility to Azoles, and Incidences of Clinical Signs of Oral Candidiasis without Culture Evidence

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains

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