Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis Inhibition
<i>Candida albicans</i> is the most dominant and prevalent cause of fungal infections in humans. Azoles are considered as first-line drugs for the treatment of these infections. However, their prolonged and insistent use has led to multidrug resistance and treatment failures. To overcome...
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MDPI AG
2022-06-01
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| Series: | Journal of Fungi |
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| Online Access: | https://www.mdpi.com/2309-608X/8/7/688 |
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| author | Irfan A. Rather Jamal S. M. Sabir Amer H. Asseri Mohmmad Younus Wani Aijaz Ahmad |
| author_facet | Irfan A. Rather Jamal S. M. Sabir Amer H. Asseri Mohmmad Younus Wani Aijaz Ahmad |
| author_sort | Irfan A. Rather |
| collection | DOAJ |
| description | <i>Candida albicans</i> is the most dominant and prevalent cause of fungal infections in humans. Azoles are considered as first-line drugs for the treatment of these infections. However, their prolonged and insistent use has led to multidrug resistance and treatment failures. To overcome this, modification or derivatization of the azole ring has led to the development of new and effective antifungal molecules. In a previous study, we reported on the development of new triazole-based molecules as potential antifungal agents against <i>Candida auris</i>. In this study, the most potent molecules from the previous study were docked and simulated with lanosterol 14-alpha demethylase enzyme. These compounds were further evaluated for in vitro susceptibility testing against <i>C. albicans</i>. In silico results revealed favorable structural dynamics of the compounds, implying that the compounds would be able to effectively bind to the target enzyme, which was further manifested by the strong interaction of the test compounds with the amino acid residues of the target enzyme. In vitro studies targeting quantification of ergosterol content revealed that pta1 was the most active compound and inhibited ergosterol production by >90% in both drug-susceptible and resistant <i>C. albicans</i> isolates. Furthermore, RT-qPCR results revealed downregulation of <i>ERG11</i> gene when <i>C. albicans</i> cells were treated with the test compound, which aligns with the decreased ergosterol content. In addition, the active triazole derivatives were also found to be potent inhibitors of biofilm formation. Both in silico and in vitro results indicate that these triazole derivatives have the potential to be taken to the next level of antifungal drug development. |
| first_indexed | 2024-03-09T13:34:36Z |
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| language | English |
| last_indexed | 2024-03-09T13:34:36Z |
| publishDate | 2022-06-01 |
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| series | Journal of Fungi |
| spelling | doaj.art-e2a3791240f54479bd47766b99099b292023-11-30T21:14:10ZengMDPI AGJournal of Fungi2309-608X2022-06-018768810.3390/jof8070688Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis InhibitionIrfan A. Rather0Jamal S. M. Sabir1Amer H. Asseri2Mohmmad Younus Wani3Aijaz Ahmad4Department of Biological Sciences, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi ArabiaDepartment of Biological Sciences, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi ArabiaBiochemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi ArabiaDepartment of Chemistry, College of Science, University of Jeddah, Jeddah 21589, Saudi ArabiaClinical Microbiology and Infectious Diseases, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg 2193, South Africa<i>Candida albicans</i> is the most dominant and prevalent cause of fungal infections in humans. Azoles are considered as first-line drugs for the treatment of these infections. However, their prolonged and insistent use has led to multidrug resistance and treatment failures. To overcome this, modification or derivatization of the azole ring has led to the development of new and effective antifungal molecules. In a previous study, we reported on the development of new triazole-based molecules as potential antifungal agents against <i>Candida auris</i>. In this study, the most potent molecules from the previous study were docked and simulated with lanosterol 14-alpha demethylase enzyme. These compounds were further evaluated for in vitro susceptibility testing against <i>C. albicans</i>. In silico results revealed favorable structural dynamics of the compounds, implying that the compounds would be able to effectively bind to the target enzyme, which was further manifested by the strong interaction of the test compounds with the amino acid residues of the target enzyme. In vitro studies targeting quantification of ergosterol content revealed that pta1 was the most active compound and inhibited ergosterol production by >90% in both drug-susceptible and resistant <i>C. albicans</i> isolates. Furthermore, RT-qPCR results revealed downregulation of <i>ERG11</i> gene when <i>C. albicans</i> cells were treated with the test compound, which aligns with the decreased ergosterol content. In addition, the active triazole derivatives were also found to be potent inhibitors of biofilm formation. Both in silico and in vitro results indicate that these triazole derivatives have the potential to be taken to the next level of antifungal drug development.https://www.mdpi.com/2309-608X/8/7/688triazole derivatives<i>C. albicans</i>ergosterolmolecular dockingsimulation |
| spellingShingle | Irfan A. Rather Jamal S. M. Sabir Amer H. Asseri Mohmmad Younus Wani Aijaz Ahmad Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis Inhibition Journal of Fungi triazole derivatives <i>C. albicans</i> ergosterol molecular docking simulation |
| title | Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis Inhibition |
| title_full | Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis Inhibition |
| title_fullStr | Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis Inhibition |
| title_full_unstemmed | Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis Inhibition |
| title_short | Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in <i>Candida albicans</i> Causing Ergosterol Biosynthesis Inhibition |
| title_sort | triazole derivatives target 14α demethylase ldm enzyme in i candida albicans i causing ergosterol biosynthesis inhibition |
| topic | triazole derivatives <i>C. albicans</i> ergosterol molecular docking simulation |
| url | https://www.mdpi.com/2309-608X/8/7/688 |
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