Transcriptional Regulation of Azole Antifungal Resistance in Candida albicans
Bibliographic record
Abstract
Candida albicans is a pathogenic fungi found in the mucosa, gastrointestinal, and urogenital tracts of humans. Oropharyngeal candidiasis (OPC), an opportunistic mucosal infection caused by C. albicans, occurs most frequently in patients infected with human immunodeficiency virus (HIV). OPC is usually treated with azole antifungals, a class of antifungals that target ergosterol biosynthesis, at low doses over long periods of time. This course of treatment allows for the development of azole resistance. Two major mechanisms of azole resistance exist in C. albicans, the up-regulation of genes encoding efflux pumps and the up-regulation of ERG11, a gene encoding the azole drug target lanosterol demethylase. The overexpression of efflux pumps remain the major contributor of azole resistance. The ATP binding cassette (ABC) transporter genes CDR1 and CDR2 have been shown to be regulated by a zinc cluster transcription factor Tac1p. A gain-of-function mutation in the gene encoding this transcription factor is responsible for the overexpression of CDR1 and CDR2. To identify the Tac1p regulon, we analyzed four matched sets of clinical isolates with gain-of-function mutations in TAC1 representing the development of CDR1- and CDR2-mediated azole resistance, using gene expression profiling. We identified genes that were consistently up-regulated coordinately with CDR1 and CDR2, including TAC1 itself. When a resistant strain disrupted for TAC1 was similarly examined, the expression of almost all of these genes returned to levels similar to those in the matched azole-susceptible isolate. Using chromatin Immunoprecipitation microarray (ChIP-chip) analysis, we found genes whose promoters were bound by Tac1p in vivo, including CDR1 and CDR2. Sequence analysis identified genes whose promoters contain the previously reported Tac1p drug-responsive element (DRE; CGGN4CGG), including TAC1. Our results show that Tac1p is constitutively bound to the promoter of its targets, including to its own promoter. They also suggest roles for Tac1p in regulating lipid metabolism (mobilization and trafficking) and oxidative stress response in C. albicans. Constitutive overexpression of the MDR1 gene, which encodes an efflux pump of the major facilitator superfamily, is another cause of resistance to fluconazole in clinical C. albicans strains. The regulator of MDR1 gene expression has not been identified or characterized. Using genome-wide gene expression profiling, we have identified a gene encoding a zinc cluster transcription factor, designated as MRR1 (multidrug resistance regulator), that was coordinately up-regulated with MDR1 in drug-resistant clinical C. albicans isolates. The disruption of MRR1 in two resistant clinical isolates abrogated MDR1 expression and multidrug resistance. MRR1 alleles
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".