ArticleAntimicrobial agents and chemotherapy2014
UPC2A is required for high-level azole antifungal resistance in Candida glabrata.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 55 citations in OpenAlex.
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- Catechin potentiates the antifungal effect of miconazole in Candida glabrata.Folia microbiologica · 2023Article
- The Microevolution of Antifungal Drug Resistance in Pathogenic Fungi.Microorganisms · 2023Review
- Meyerozyma guilliermondii species complex: review of current epidemiology, antifungal resistance, and mechanisms.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2022Review
- The Set1 Histone H3K4 Methyltransferase Contributes to Azole Susceptibility in a Species-Specific Manner by Differentially Altering the Expression of Drug Efflux Pumps and the Ergosterol Gene Pathway.Antimicrobial agents and chemotherapy · 2022Article
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- Copper Acts Synergistically With Fluconazole inFrontiers in microbiology · 2022Article
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- Two Sequential Clinical Isolates ofAntibiotics (Basel, Switzerland) · 2021Article
- The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways.PLoS genetics · 2021Article
- Antifungal Drug Resistance: Molecular Mechanisms inChemical reviews · 2021Review
- Identification of Essential Genes and Fluconazole Susceptibility Genes inG3 (Bethesda, Md.) · 2020Article
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8 authors at 3 institutions in 1 country.
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Abstract
Candida glabrata, the second most common cause of Candida infections, is associated with high rates of mortality and often exhibits resistance to the azole class of antifungal agents. Upc2 and Ecm22 in Saccharomyces cerevisiae and Upc2 in Candida albicans are the transcriptional regulators of ERG11, the gene encoding the target of azoles in the ergosterol biosynthesis pathway. Recently two homologs for these transcription factors, UPC2A and UPC2B, were identified in C. glabrata. One of these, UPC2A, was shown to influence azole susceptibility. We hypothesized that due to the global role for Upc2 in sterol biosynthesis in S. cerevisiae and C. albicans, disruption of UPC2A would enhance the activity of fluconazole in both azole-susceptible dose-dependent (SDD) and -resistant C. glabrata clinical isolates. To test this hypothesis, we constructed mutants with disruptions in UPC2A and UPC2B alone and in combination in a matched pair of clinical azole-SDD and -resistant isolates. Disruption of UPC2A in both the SDD and resistant isolates resulted in increased susceptibility to sterol biosynthesis inhibitors, including a reduction in fluconazole MIC and minimum fungicidal concentration, enhanced azole activity by time-kill analysis, a decrease in ergosterol content, and downregulation of baseline and inducible expression of several sterol biosynthesis genes. Our results indicate that Upc2A is a key regulator of ergosterol biosynthesis and is essential for resistance to sterol biosynthesis inhibitors in C. glabrata. Therefore, the UPC2A pathway may represent a potential cotherapeutic target for enhancing azole activity against this organism.
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