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Antifungal activity of fibrate-based compounds and substituted pyrroles inhibiting the enzyme 3-hydroxy-methyl-glutaryl-CoA reductase of Candida glabrata (CgHMGR), and decreasing yeast viability and ergosterol synthesis

Damián A. Madrigal-Aguilar, Adilene Gonzalez-Silva, Blanca Rosales-Acosta, Celia Bautista-Crescencio, Jossué Ortiz-Álvarez, Carlos H. Escalante, Jaime Sánchez-Navarrete, César Hernández-Rodríguez, Germán Chamorro-Cevallos, Joaquín Tamariz, View ORCID ProfileLourdes Villa-Tanaca
doi: https://doi.org/10.1101/2021.09.14.460412
Damián A. Madrigal-Aguilar
aDepartamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico., MX
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Adilene Gonzalez-Silva
bDepartamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico
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Blanca Rosales-Acosta
bDepartamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico
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Celia Bautista-Crescencio
bDepartamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico
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Jossué Ortiz-Álvarez
bDepartamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico
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Carlos H. Escalante
aDepartamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico., MX
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Jaime Sánchez-Navarrete
cLaboratorio de Investigación Microbiológica, Hospital Juárez de México, Av. Instituto Politécnico Nacional Núm. 5160, México City, Mexico
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César Hernández-Rodríguez
bDepartamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico
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Germán Chamorro-Cevallos
dDepartamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, México City, Mexico
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Joaquín Tamariz
aDepartamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico., MX
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  • For correspondence: mvillat@ipn.mx lourdesvillatanaka@gmail.com jtamarizm@gmail.com
Lourdes Villa-Tanaca
bDepartamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, CP 11340, Mexico City, Mexico
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  • ORCID record for Lourdes Villa-Tanaca
  • For correspondence: mvillat@ipn.mx lourdesvillatanaka@gmail.com jtamarizm@gmail.com
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ABSTRACT

Due to the emergence of multi-drug resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase (CgHMGR), and thus affect ergosterol synthesis and yeast viability. One series of synthetic antifungal compounds were analogues to fibrates, a second series had substituted 1,2-dihydroquinolines and the third series included substituted pyrroles. α-asarone-related compounds 1c and 5b with a pyrrolic core were selected as the best antifungal candidates. Both inhibited the growth of fluconazole-resistant C. glabrata 43 and fluconazole-susceptible C. glabrata CBS 138. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 strain and after the 1c (versus 5b) treatment. Given that the compounds decreased the ergosterol concentration in the yeast strains, they probably target the ergosterol synthesis. According to the docking analysis, the inhibitory effect of the 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of CgHMGR. Since 1c displayed higher binding energy than α-asarone and 5b, it is a good candidate for further research, which should include structural modifications to increase its specificity and potency as well as in vivo studies on its effectiveness at a therapeutic dose.

HIGHLIGHTS

  1. Fibrate-based and pyrrole-containing compounds were tested as C. glabrata inhibitors.

  2. The best inhibitor from fibrate was 1c and from pyrroles was 5b.

  3. These agents inhibited C. glabrata growth better than the reference antifungals.

  4. They also inhibited ergosterol synthesis by the two C. glabrata strains tested. Experimental

  • ABBREVIATIONS

    ANOVA
    analysis of variance
    CgHMGR
    3-hydroxy-methyl-glutaryl-CoA reductase in Candida glabrata
    CLSI
    Clinical and Laboratory Standards Institute
    DHE
    dihydroxy-ergosterol
    DMSO
    dimethyl sulfoxide
    HMGR
    3-hydroxy-methyl-glutaryl-CoA reductase
    KOH
    potassium hydroxide
    NBS
    N-bromosuccinimide
    SD
    standard deviation
    YPD
    yeast extract-peptone-dextrose medium
  • Copyright 
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    Posted September 16, 2021.
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    Antifungal activity of fibrate-based compounds and substituted pyrroles inhibiting the enzyme 3-hydroxy-methyl-glutaryl-CoA reductase of Candida glabrata (CgHMGR), and decreasing yeast viability and ergosterol synthesis
    Damián A. Madrigal-Aguilar, Adilene Gonzalez-Silva, Blanca Rosales-Acosta, Celia Bautista-Crescencio, Jossué Ortiz-Álvarez, Carlos H. Escalante, Jaime Sánchez-Navarrete, César Hernández-Rodríguez, Germán Chamorro-Cevallos, Joaquín Tamariz, Lourdes Villa-Tanaca
    bioRxiv 2021.09.14.460412; doi: https://doi.org/10.1101/2021.09.14.460412
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    Antifungal activity of fibrate-based compounds and substituted pyrroles inhibiting the enzyme 3-hydroxy-methyl-glutaryl-CoA reductase of Candida glabrata (CgHMGR), and decreasing yeast viability and ergosterol synthesis
    Damián A. Madrigal-Aguilar, Adilene Gonzalez-Silva, Blanca Rosales-Acosta, Celia Bautista-Crescencio, Jossué Ortiz-Álvarez, Carlos H. Escalante, Jaime Sánchez-Navarrete, César Hernández-Rodríguez, Germán Chamorro-Cevallos, Joaquín Tamariz, Lourdes Villa-Tanaca
    bioRxiv 2021.09.14.460412; doi: https://doi.org/10.1101/2021.09.14.460412

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