ArticleAntimicrobial agents and chemotherapy2014
Novel antifungal drug discovery based on targeting pathways regulating the fungus-conserved Upc2 transcription factor.
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 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
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- Therapeutic potential of morpholine-based compounds in neurodegenerative diseases: SAR insights and analysis.Future medicinal chemistry · 2025Review
- Editorial: Lipids in host microbe interaction.Frontiers in cellular and infection microbiology · 2022Article
- The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways.PLoS genetics · 2021Article
- Antifungal drug screening: thinking outside the box to identify novel antifungal scaffolds.Current opinion in microbiology · 2020Review
- Transcriptional control of hyphal morphogenesis in Candida albicans.FEMS yeast research · 2020Review
- Rational Discovery of (+) (S) Abscisic Acid as a Potential Antifungal Agent: a Repurposing Approach.Scientific reports · 2018Article
- The antifungal pipeline: a reality check.Nature reviews. Drug discovery · 2017Review
- From Lipid Homeostasis to Differentiation: Old and New Functions of the Zinc Cluster Proteins Ecm22, Upc2, Sut1 and Sut2.International journal of molecular sciences · 2017Review
- The synthesis, regulation, and functions of sterols in Candida albicans: Well-known but still lots to learn.Virulence · 2016Review
- A complex game of hide and seek: the search for new antifungals.MedChemComm · 2016Article
- Sterol Biosynthesis and Azole Tolerance Is Governed by the Opposing Actions of SrbA and the CCAAT Binding Complex.PLoS pathogens · 2016Article
- Article
- Integrated analysis identifies interaction patterns between small molecules and pathways.BioMed research international · 2014Article
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Infections by Candida albicans and related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level and UPC2-LacZ gene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expression in vivo. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs.
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