Articles producció científica> Ciències Mèdiques Bàsiques

Sterol Biosynthesis and Azole Tolerance Is Governed by the Opposing Actions of SrbA and the CCAAT Binding Complex

  • Datos identificativos

    Identificador: PC:1834
    Handle: https://hdl.handle.net/20.500.11797/PC1834
    Autores:
    Javier CapillaFabio GsallerPeter HortschanskyTakanori FurukawaPaul D. CarrBharat RashChristoph MüllerFranz BracherPaul BowyerHubertus HaasAxel A. BrakhageMichael J. Bromley
    Resumen:
    Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic arsenal. However, resistance to this class of drugs, particularly in the major human mould pathogen Aspergillus fumigatus, is emerging and reaching levels that have prompted some to suggest that there is a realistic probability that they will be lost for clinical use. The dominating class of pan-azole resistant isolates is characterized by the presence of a tandem repeat of at least 34 bases (TR34) within the promoter of cyp51A, the gene encoding the azole drug target sterol C14-demethylase. Here we demonstrate that the repeat sequence in TR34 is bound by both the sterol regulatory element binding protein (SREBP) SrbA, and the CCAAT binding complex (CBC). We show that the CBC acts complementary to SrbA as a negative regulator of ergosterol biosynthesis and show that lack of CBC activity results in increased sterol levels via transcriptional derepression of multiple ergosterol biosynthetic genes including those coding for HMG-CoA-synthase, HMG-CoA-reductase and sterol C14-demethylase. In agreement with these findings, inactivation of the CBC increased tolerance to different classes of drugs targeting ergosterol biosynthesis including the azoles, allylamines (terbinafine) and statins (simvastatin). We reveal that a clinically relevant mutation in HapE (P88L) significantly impairs the binding affinity of the CBC to its target site. We identify that the mechanism underpinning TR34 driven overexpression of cyp51A results from duplication of SrbA but not CBC binding sites and show that deletion of the 34 mer results in lack of cyp51A expression and increased azole susceptibility similar to a cyp51A null mutant. Finally we show that strains lacking a functional CBC are seve

  • Otros:

    Autor según el artículo: Javier Capilla; Fabio Gsaller; Peter Hortschansky; Takanori Furukawa; Paul D. Carr; Bharat Rash; Christoph Müller; Franz Bracher; Paul Bowyer; Hubertus Haas; Axel A. Brakhage; Michael J. Bromley
    Departamento: Ciències Mèdiques Bàsiques
    Autor/es de la URV: CAPILLA LUQUE, JAVIER
    Palabras clave: cell extract pyrrole derivative CCAAT binding factor
    Resumen: Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic arsenal. However, resistance to this class of drugs, particularly in the major human mould pathogen Aspergillus fumigatus, is emerging and reaching levels that have prompted some to suggest that there is a realistic probability that they will be lost for clinical use. The dominating class of pan-azole resistant isolates is characterized by the presence of a tandem repeat of at least 34 bases (TR34) within the promoter of cyp51A, the gene encoding the azole drug target sterol C14-demethylase. Here we demonstrate that the repeat sequence in TR34 is bound by both the sterol regulatory element binding protein (SREBP) SrbA, and the CCAAT binding complex (CBC). We show that the CBC acts complementary to SrbA as a negative regulator of ergosterol biosynthesis and show that lack of CBC activity results in increased sterol levels via transcriptional derepression of multiple ergosterol biosynthetic genes including those coding for HMG-CoA-synthase, HMG-CoA-reductase and sterol C14-demethylase. In agreement with these findings, inactivation of the CBC increased tolerance to different classes of drugs targeting ergosterol biosynthesis including the azoles, allylamines (terbinafine) and statins (simvastatin). We reveal that a clinically relevant mutation in HapE (P88L) significantly impairs the binding affinity of the CBC to its target site. We identify that the mechanism underpinning TR34 driven overexpression of cyp51A results from duplication of SrbA but not CBC binding sites and show that deletion of the 34 mer results in lack of cyp51A expression and increased azole susceptibility similar to a cyp51A null mutant. Finally we show that strains lacking a functional CBC are severely attenuated for pathogenicity in a pulmonary and systemic model of aspergillosis.
    Grupo de investigación: Unitat de Micologia i Microbiologia Ambiental
    Áreas temáticas: Health sciences Ciencias de la salud Ciències de la salut
    Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 1553-7366
    Identificador del autor: N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D; N/D
    Fecha de alta del registro: 2016-09-20
    Página final: 22p
    Volumen de revista: 12
    Versión del articulo depositado: info:eu-repo/semantics/publishedVersion
    URL Documento de licencia: https://repositori.urv.cat/ca/proteccio-de-dades/
    Entidad: Universitat Rovira i Virgili
    Año de publicación de la revista: 2016
    Página inicial: Art.num. e1005775
    Tipo de publicación: Article Artículo Article

  • Palabras clave:

    Fongs patògens
    Micologia mèdica
    cell extract
    pyrrole derivative
    CCAAT binding factor
    Health sciences
    Ciencias de la salud
    Ciències de la salut
    1553-7366

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